Oral peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory bowel diseases

ABSTRACT

The present invention provides novel peptide inhibitors of the interleukin-23 receptor, and related compositions and methods of using these peptide inhibitors to treat or prevent a variety of diseases and disorders, including inflammatory bowel disease.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. application Ser. No.14/800,627, filed Jul. 15, 2015; which claims priority to U.S.Provisional Application No. 62/025,899, filed on Jul. 17, 2014, U.S.Provisional Application No. 62/119,685, filed on Feb. 23, 2015, and U.S.Provisional Application No. 62/119,688, filed on Feb. 23, 2015, each ofwhich is incorporated by reference herein in its entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Feb. 24, 2017, isnamed PRTH-002-03US_ST25.txt and is 505 KB in size.

FIELD OF THE INVENTION

The present invention relates to novel peptide inhibitors of theinterleukin-23 receptor, and their use to treat or prevent a variety ofdiseases and disorders, including inflammatory bowel disease, Crohn'sdisease and psoriasis.

BACKGROUND

The interleukin-23 (IL-23) cytokine has been implicated as playing acrucial role in the pathogenesis of autoimmune inflammation and relateddiseases and disorders, such as multiple sclerosis, asthma, rheumatoidarthritis, psoriasis, and inflammatory bowel diseases (IBDs), e.g.,ulcerative colitis and Crohn's disease. Studies in acute and chronicmouse models of IBD revealed a primary role of IL-23R and downstreameffector cytokines in disease pathogenesis. IL-23R is expressed onvarious adaptive and innate immune cells including Th17 cells, γδ Tcells, natural killer (NK) cells, dendritic cells, macrophages, andinnate lymphoid cells, which are found abundantly in the intestine. Atthe intestine mucosal surface, the gene expression and protein levels ofIL-23R are found to be elevated in IBD patients. It is believed thatIL-23 mediates this effect by promoting the development of a pathogenicCD4⁺ T cell population that produces IL-6, IL-17, and tumor necrosisfactor (TNF).

Production of IL-23 is enriched in the intestine, where it is believedto play a key role in regulating the balance between tolerance andimmunity through T-cell-dependent and T-cell-independent pathways ofintestinal inflammation through effects on T-helper 1 (Th1) andTh17-associated cytokines, as well as restraining regulatory T-cellresponses in the gut, favoring inflammation. In addition, polymorphismsin the IL-23 receptor (IL-23R) have been associated with susceptibilityto IBDs, further establishing the critical role of the IL-23 pathway inintestinal homeostasis.

Psoriasis, a chronic skin disease affecting about 2%-3% of the generalpopulation has been shown to be mediated by the body's T cellinflammatory response mechanisms. 11-23 has one of several interleukinsimplicated as a key player in the pathogenesis of psoriasis, purportedlyby maintaining chronic autoimmune inflammation via the induction ofinterleukin-17, regulation of T memory cells, and activation ofmacrophages. Expression of IL-23 and IL-23R has been shown to beincreased in tissues of patients with psoriasis, and antibodies thatneutralize IL-23 showed IL-23-dependent inhibition of psoriasisdevelopment in animal models of psoriasis.

IL-23 is a heterodimer composed of a unique p19 subunit and the p40subunit of IL-12, which is a cytokine involved in the development ofinterferon-γ (IFN-γ)-producing T helper 1 (TH1) cells. Although IL-23and IL-12 both contain the p40 subunit, they have different phenotypicproperties. For example, animals deficient in IL-12 are susceptible toinflammatory autoimmune diseases, whereas IL-23 deficient animals areresistant, presumably due to a reduced number of CD4⁺ T cells producingIL-6, IL-17, and TNF in the CNS of IL-23-deficient animals. IL-23 bindsto IL-23R, which is a heterodimeric receptor composed of IL-12Rβ1 andIL-23R subunits. Binding of IL-23 to IL-23R activates the Jak-statsignaling molecules, Jak2, Tyk2, and Stat1, Stat 3, Stat 4, and Stat 5,although Stat4 activation is substantially weaker and differentDNA-binding Stat complexes form in response to IL-23 as compared withIL-12. IL-23R associates constitutively with Jak2 and in aligand-dependent manner with Stat3. In contrast to IL-12, which actsmainly on naive CD4(+) T cells, IL-23 preferentially acts on memoryCD4(+) T cells.

Efforts have been made to identify therapeutic moieties that inhibit theIL-23 pathway, for use in treating IL-23-related diseases and disorders.A number of antibodies that bind to IL-23 or IL-23R have beenidentified, including ustekinumab, a humanized antibody that bindsIL-23, which has been approved for the treatment of psoriasis. Morerecently, polypeptide inhibitors that bind to IL-23R and inhibit thebinding of IL-23 to IL-23R have been identified (see, e.g., US PatentApplication Publication No. US2013/0029907). Clinical trials in Crohn'sDisease or psoriasis with ustekinumab and briakinumab (which target thecommon p40 subunit) and tildrakizumab, guselkumab, MEDI2070, andBI-655066 (which target the unique p19 subunit of IL-23) highlight thepotential of IL-23 signaling blockade in treatment of human inflammatorydiseases. While these findings are promising, challenges remain withrespect to identifying stable and selective agents that preferentiallytarget the IL-23 pathway in the intestine, which can be used for thetreatment of intestinal inflammation, such as intestinal bowel diseases,including Crohn's disease, ulcerative colitis and related disorders.

Clearly, there remains a need in the art for new therapeutics targetingthe IL-23 pathway, which may be used to treat and preventIL-23-associated diseases, including those associated with autoimmuneinflammation in the intestinal tract. In addition, compounds and methodsfor specific targeting of IL-23R from the luminal side of the gut mayprovide therapeutic benefit to IBD patients suffering from localinflammation of the intestinal tissue. The present invention addressesthese needs by providing novel peptide inhibitors that bind IL-23R toinhibit IL-23 binding and signaling and which are suitable for oraladministration.

BRIEF SUMMARY OF THE INVENTION

The present invention provides inter alia novel peptide inhibitors ofIL-23R and related methods of use.

In a first aspect, the present invention provides a peptide inhibitor ofan interleukin-23 receptor, or a pharmaceutically acceptable salt orsolvate thereof, wherein the peptide inhibitor comprises an amino acidsequence of Formula (Xa):

X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (Xa),

wherein:X1, X2 and X3 are any amino acid or absentX4 is any amino acid or chemical moiety capable of forming a bond withX9;X5, X6, X7 and X8 are any amino acid;X9 is any amino acid or chemical moiety capable of forming a bond withX4;X10, X11, X12, X13, X14 and X15 are any amino acid; andX16, X17, X18, X19 and X20 are any amino acid or absent;

wherein the peptide inhibitor is cyclized via a bond between X4 and X9,and

wherein the peptide inhibitor inhibits the binding of an interleukin-23(IL-23) to an IL-23 receptor.

In certain embodiments of Xa:

X1 is absent; X2 is absent; X3 is absent; X4 is Cys, Abu or Pen; X5 isAla, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap(Ac), Gly, Lys, Asn, N-MeGln,N-MeArg, Orn, Gln, Arg, Ser or Thr; X6 is Asp or Thr; X7 is Trp or6-Chloro-Trp; X8 is Glu, Gln or Val; X9 is Cys, Abu or Pen; X10 is2-Nal, a Phe analog, Tyr, or a Tyr analog; X11 is 1-Nal, 2-Nal,Phe(3,4-dimethoxy), 5-HydroxyTrp, Phe(3,4-Cl₂), Trp or Tyr(3-tBu); X12is 3-Pal, Acpc, Acbc, Acvc, Achc, Agp, Aib, α-DiethylGly, α-MeLys,α-MeLys(Ac), α-MeLeu, α-MeOrn, α-MeSer, α-MeVal, Cav, Cha, Cit, Cpa,D-Asn, Glu, His, hLeu, hArg, Lys, Leu, Octgly, Orn,4-amino-4-carboxy-piperidine, Arg, Ser, Thr or THP; X13 is Cit, Asp,Dab, Dap, Phe, His, Dap(Peg2-Ac), Dap(pyroglutaric acid), Glu, HomoArg,Lys, Lys(Ac), Lys(Benzoic acid), Lys(glutaric acid), Lys(IVA),Lys(Peg4-isoGlu-Palm), Lys(pyroglutaric acid), Lys(succinic acid), Asn,Orn, Gln, Arg, Thr or Val; X14 is Asp, Dab(Ac), Dap(Ac), Phe, His,Lys(Ac), Met, Asn(isobutyl), Gln, Arg, Tyr or Asp(1,4-diaminobutane);and X15 is Ala, βAla, Glu, Gly, Asn, Gln, Arg or Ser.

In certain embodiments of Xa: X1 is absent; X2 is absent; X3 is absent;X4 is Cys, Abu or Pen; X5 is Ala, α-MeOrn, α-MeSer, Cit, Dap, Dab,Dap(Ac), Gly, Lys, Asn, Orn, Gln, Arg, Ser or Thr; X6 is Asp or Thr; X7is Trp or 6-Chloro-Trp; X8 is Gln or Val; X9 is Cys, Abu or Pen; X10 is2-Nal, a Phe analog, Tyr, or a Tyr analog; X11 is 1-Nal, 2-Nal,Phe(3,4-dimethoxy), 5-HydroxyTrp, Phe(3,4-Cl₂), Trp or Tyr(3-tBu); X12is 3-Pal, Acpc, Acbc, Acvc, Achc, Agp, Aib, α-DiethylGly, α-MeLys,α-MeLys(Ac), α-MeLeu, α-MeOrn, α-MeSer, α-MeVal, Cav, Cha, Cit, Cpa,D-Asn, His, hLeu, hArg, Lys, Leu, Octgly, Orn,4-amino-4-carboxy-piperidine, or THP; X13 is Cit, Asp, Dab, Dap, Phe,His, Dap(Peg2-Ac), Dap(pyroglutaric acid), Glu, hArg, Lys, Lys(Ac),Lys(Benzoic acid), Lys(glutaric acid), Lys(IVA), Lys(Peg4-isoGlu-Palm),Lys(pyroglutaric acid), Lys-(succinic acid), Asn, Orn, Gln, Arg, Thr orVal; X14 is Dab(Ac), Dap(Ac), Phe, His, Lys(Ac), Met, Asn, Gln, Arg, orTyr; and X15 is Ala, betaAla, Gly, Asn, Gln, or Ser.

In certain embodiments of Xa: X1 is absent; X2 is absent; X3 is absent;X4 is Cys, Abu or Pen; X5 is Dap, Dap(Ac), Gly, Lys, Gln, Arg, Ser, Thror Asn; X6 is Thr; X7 is Trp or 6-Chloro-Trp; X8 is Gln; X9 is Cys, Abuor Pen; X10 is 2-Nal, a Phe analog, Tyr, or a Tyr analog; X11 is 1-Nal,2-Nal, Phe(3,4-dimethoxy), Phe(3,4-Cl₂), or Trp; X12 is Acpc, Acbc,Acvc, Achc, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac), α-MeLeu, α-MeOrn,α-MeSer, α-MeVal, Cha, Cit, hLeu, Lys, Leu, Arg or THP; X13 is Cit, Asp,Dap, Dap(Peg2-Ac), Dap(pyroglutaric acid), Glu, hArg, Lys, Lys(Ac),Lys(Benzoic acid), Lys(glutaric acid), Lys(IVA), Lys(Peg4-isoGlu-Palm),Lys(pyroglutaric acid), Lys-(succinic acid), Asn, Orn, Gln, Arg, or Val;X14 is Dab(Ac), Dap(Ac), His, Lys(Ac), Asn, Gln, or Tyr; and X15 is Ala,betaAla, Gly, Asn, Gln, or Ser.

In certain embodiments of Xa: X1 is absent; X2 is absent; X3 is absent;X4 is Cys, Abu or Pen; X5 is Dap, Dap(Ac), Gln, Ser, Thr or Asn; X6 isThr; X7 is Trp; X8 is Gln; X9 is Cys, Abu or Pen; X10 is a Phe analog,Tyr, or a Tyr analog; X11 is 2-Nal or Trp; X12 is Acpc, Acbc, Acvc,Achc, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac), α-MeLeu, α-MeOrn,α-MeSer, α-MeVal, hLeu, Leu, or THP; X13 is Cit, Asp, Glu, Lys, Lys(Ac),Asn, or Gln; X14 is Dab(Ac), Asn, or His; and X15 is Ala, betaAla, Gly,Asn, or Gln.

In certain embodiments of Xa: X4 is Cys, Pen, hCys, D-Pen, D-Cys,D-hCys, Met, Glu, Asp, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu,D-Lys, Sec, 2-chloromethylbenzoic acid, mercapto-propanoic acid,mercapto-butyric acid, 2-chloro-acetic acid, 3-choropropanoic acid,4-chlorobutyric acid, 3-chloroisobutyric acid, Abu, β-azido-Ala-OH,propargylglycine, 2-(3′-butenyl)glycine, 2-allylglycine,2-(3′-butenyl)glycine, 2-(4′-pentenyl)glycine, 2-(5′-hexenyl)glycine, orAbu; X7 is Trp, Glu, Gly, Ile, Asn, Pro, Arg, Thr or OctGly, or acorresponding α-methyl amino acid form of any of the foregoing; X9 isCys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab, D-Dap,D-Dab, D-Asp, D-Glu, D-Lys, Asp, Leu, Val, Phe, or Ser, Sec, Abu,β-azido-Ala-OH, propargylglycine, 2-2-allylglycine,2-(3′-butenyl)glycine, 2-(4′-pentenyl)glycine, Ala, hCys, Abu, Met,MeCys, (D)Tyr or 2-(5′-hexenyl)glycine; X10 is Tyr, Phe(4-OMe), 1-Nal,2-Nal, Aic, α-MePhe, Bip, (D)Cys, Cha, DMT, (D)Tyr, Glu, His,hPhe(3,4-dimethoxy), hTyr, N-Me-Tyr, Trp, Phe(4-CONH₂), Phe(4-phenoxy),Thr, Tic, Tyr(3-tBu), Phe(4-tBu), Phe(4-CN), Phe(4-Br), Phe(4-NH₂),Phe(4-F), Phe(3,5-F₂), Phe(4-CH₂CO₂H), Phe(penta-F), Phe(3,4-Cl₂),Phe(4-CF₃), Phe(4-OCH₃), Bip, Cha, 4-PyridylAlanine, βhTyr, OctGly,Phe(4-N₃), Phe(4-Br), Phe[4-(2-aminoethoxy)] or Phe, a Phe analog, a Tyranalog, or a corresponding α-methyl amino acid form of any of theforegoing; X11 is 2-Nal, 1-Nal, 2,4-dimethylPhe, Bip, Phe(3,4-Cl₂), Phe(3,4-F₂), Phe(4-CO₂H), βhPhe(4-F), α-Me-Trp, 4-phenylcyclohexyl,Phe(4-CF₃), α-MePhe, βNal, βhPhe, βhTyr, βhTrp, Nva(5-phenyl), Phe, His,hPhe, Tic, Tqa, Trp, Tyr, Phe(4-OMe), Phe(4-Me),Trp(2,5,7-tri-tert-Butyl), Phe(4-Oallyl), Tyr(3-tBu), Phe(4-tBu),Phe(4-guanidino, Phe(4-OBzl), Octgly, Glu(Bzl), 4-Phenylbenzylalanine,Phe[4-(2-aminoethoxy)], 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp,1,2,3,4-tetrahydro-norharman, Phe(4-CONH₂), Phe(3,4-Dimethoxy),Phe(2,3-Cl₂), Phe(2,3-F₂), Phe(4-F), 4-phenylcyclohexylalanine, Bip, ora corresponding α-methyl amino acid form of any of the foregoing; X12 isHis, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal,t-butyl-Ala, 4-amino-4-carboxy-tetrahydropyran, Achc Acpc, Acvc, Acbc,Agp, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac), α-Me-Leu, α-MeOrn,α-MeSer, α-MeVal, Aib, D-Ala, (D)Asn, (D)Asp, (D)Leu, (D)Phe, (D)Tyr,Aib, α-MeLeu, α-MeOrn, Aib, β-Ala, βhAla, βhArg, βhLeu, βhVal,β-spiro-pip, Glu, hArg, Ile, Lys, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln,Ser, Thr, Tle, t-butyl-Gly, or a corresponding α-methyl amino acid formof any of the foregoing; X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Arg,Orn, Val, βhAla, Lys(Ac), (D)Asn, (D)Leu, (D)Phe, (D)Thr, Ala, α-MeLeu,Aib, β-Ala, β-Glu, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Dab, Dap,α-DiethylGly, hLeu, Asn, Ogl, Pro, Gln, Ser, β-spiro-pip, Thr, Tba, Tleor Aib, Cit, hArg, Lys, Asn, Orn, Gln or a corresponding α-methyl aminoacid form of any of the foregoing; X14 is Phe, Tyr, Glu, Gly, His, Lys,Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, TicβhPhe, Arg, Lys(Ac), His;Dap(Ac), Dab(Ac), Asp or a corresponding α-methyl amino acid form of anyof the foregoing; X15 is Gly, Ser, Thr, Gln, Ala, (D)Ala, (D)Asn,(D)Asp, (D)Leu, (D)Phe, (D)Thr, Aea, Asp, Asn, Glu, Phe, Gly, Lys, Leu,Pro, Arg, β-Ala, Sarc, or a corresponding α-methyl amino acid form ofany of the foregoing; X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba, Gly,Ser, Pro, Asn, Thr or absent, or a corresponding α-methyl amino acidform of any of the foregoing; and X17 is Leu, Lys, Arg, Glu, Ser, Gly,Gln or absent, or a corresponding α-methyl amino acid form of any of theforegoing.

In certain embodiments of peptide inhibitors of Xa, the bond is adisulfide bond, a thioether bond, a lactam bond, a triazole ring, aselenoether bond, a diselenide bond, or an olefin bond.

In particular embodiments of peptide inhibitors of Xa, X4 is Cys and X9is Cys, and the bond is a disulfide bond. In particular embodiments, X4is Pen and X9 is Pen, and the bond is a disulfide bond. In certainembodiments: X7 is Trp; X10 is Phe, Tyr, a Phe analog, or a Tyr analog;X11 is Trp, 1-Nal or 2-Nal; and X12 is Aib, α-Me-Lys, α-Me-Leu, Achc,Acvc, Acpc, Acbc or THP. In certain embodiments: X7 is Trp; X10 is Phe,Tyr, a Phe analog, or a Tyr analog; X11 is Trp, 1-Nal or 2-Nal; and X12is Aib, α-Me-Lys or α-Me-Leu. In particular embodiments, the peptideinhibitor comprises any of the following the amino acid sequences:Pen-Q-T-W-Q-Pen-[Phe(4-OMe)]-[2-Nal]α-Me-Lys]-E-N-G (SEQ ID NO: 254);Pen-N-T-W-Q-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys(Ac)]-N-N(SEQID NO: 255);Pen-Q-T-W-Q-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeuHLys(Ac)]-N-N(SEQID NO: 256); orPen-Q-T-W-Q-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N-N(SEQ IDNO: 257), wherein the peptide inhibitor comprises a disulfide bondbetween the two Pen amino acids.

In particular embodiments of peptide inhibitors of Xa, X4 is an aminoacid, aliphatic acid, alicyclic acid or modified 2-methyl aromatic acidhaving a carbon side chain capable of forming a thioether bind with X9;X9 is a sulfur-containing amino acid capable of forming a thioether bondwith X4, and the bond between X4 and X9 is a thioether bond. In certainembodiments, X4 is Abu, 2-chloromethylbenzoic acid, mercapto-propanoicacid, mercapto-butyric acid, 2-chloro-acetic acid, 3-chloro-propanoicacid, 4-chloro-butyric acid, 3-chloro-isobutyric acid; and X9 is Abu,Cys, Pen, hCys, D-Pen, D-Cys, or D-hCys. In certain embodiments, X4 isAbu; and X9 is Cys. In certain embodiments, X7 is Trp; X10 is Phe, Tyr,a Phe analog, or a Tyr analog; X11 is Trp, 1-Nal or 2-Nal; and X12 isα-Me-Lys, α-Me-Leu, α-Me-Ser, α-Me-Val, Achc, Acvc, Acpc, Acbc, or[4-amino-4-carboxy-tetrahydropyran]. In certain embodiments, X7 is Trp;X10 is Phe, Tyr, a Phe analog, or a Tyr analog; X11 is Trp, 1-Nal or2-Nal; and X12 is α-Me-Lys or [4-amino-4-carboxy-tetrahydropyran]. Inparticular embodiments, the peptide inhibitor comprises any of thefollowing amino acid sequences:[Abu]-Q-T-W-Q-C-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-E-N-G (SEQ ID NO: 258);[Abu]-Q-T-W-Q-C-[Phe(4-(2-aminoethoxy))]-W-[α-MeLys]-E-N-G (SEQ ID NO:259); or[Abu]-Q-T-W-Q-C-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-E-N-N(SEQID NO: 260), wherein the peptide inhibitor comprises a thioether bondbetween the Abu and the C.

In certain embodiments of peptide inhibitors of Xa: X4 is Pen, Cys orhCys; X5 is any amino acid; X6 is any amino acid; X7 is Trp, Bip, Gln,His, Glu(Bzl), 4-Phenylbenzylalanine, Tic, Phe[4-(2-aminoethoxy)],Phe(3,4-Cl₂), Phe(4-OMe), 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp,α-Me-Trp, 1,2,3,4-tetrahydro-norharman, Phe(4-CO₂H), Phe(4-CONH₂),Phe(3,4-Dimethoxy), Phe(4-CF₃), Phe(4-tBu), ββ-diPheAla, Glu, Gly, Ile,Asn, Pro, Arg, Thr or Octgly, or a corresponding α-methyl amino acidform of any of the foregoing; X8 is any amino acid; X9 is Pen, Cys orhCys; X10 is 1-Nal, 2-Nal, Aic, Bip, (D)Cys, Cha, DMT, (D)Tyr, Glu, Phe,His, Trp, Thr, Tic, Tyr, 4-pyridylAla, Octgly, a Phe analog or a Tyranalog (optionally, Phe(3,4-F₂), Phe(3,4-Cl₂), F(3-Me),Phe[4-(2-aminoethoxy)], Phe[4-(2-(acetyl-aminoethoxy)], Phe(4-Br),Phe(4-CONH₂), Phe(4-Cl), Phe(4-CN), Phe(4-guanidino), Phe(4-Me),Phe(4-NH₂), Phe(4-N₃), Phe(4-OMe), or Phe(4-OBzl)), or a correspondingα-methyl amino acid form of any of the foregoing; X11 is 2-Nal, 1-Nal,2,4-dimethylPhe, Bip, Phe(3,4-Cl₂), Phe (3,4-F₂), Phe(4-CO₂H),βhPhe(4-F), α-Me-Trp, 4-phenylcyclohexyl, Phe(4-CF₃), α-MePhe, βNal,βhPhe, βhTyr, βhTrp, Nva(5-phenyl), Phe, His, hPhe, Tic, Tqa, Trp, Tyr,Phe(4-OMe), Phe(4-Me), Trp(2,5,7-tri-tert-Butyl), Phe(4-Oallyl),Tyr(3-tBu), Phe(4-tBu), Phe(4-guanidino, Phe(4-OBzl), Octgly, Glu(Bzl),4-Phenylbenzylalanine, Phe[4-(2-aminoethoxy)], 5-Hydroxy-Trp,6-Chloro-Trp, N-MeTrp, 1,2,3,4-tetrahydro-norharman, Phe(4-CONH₂),Phe(3,4-OMe₂) Phe(2,3-Cl₂), Phe(2,3-F₂), Phe(4-F),4-phenylcyclohexylalanine or Bip, or a corresponding α-methyl amino acidform of any of the foregoing; X12 is α-MeLys, α-MeOrn, α-MeLeu, α-MeVal,4-amino-4-carboxy-tetrahydropyran, Achc, Acpc, Acbc, Acvc, MeLeu, Aib,(D)Ala, (D)Asn, (D)Leu, (D)Asp, (D)Phe, (D)Thr, 3-Pal, Aib, β-Ala,βhGlu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Dab, Dap,α-DiethylGly, Glu, Phe, hLeu, hArg, hLeu, Ile, Lys, Leu, Asn, N-MeLeu,N-MeArg, Ogl, Orn, Pro, Gln, Arg, Ser, Thr or Tle, or a correspondingα-methyl amino acid form of any of the foregoing; X13 is Lys(Ac),(D)Asn, (D)Leu, (D)Thr, (D)Phe, Ala, Aib, α-MeLeu, β-Ala, βhGlu, βhAla,βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Lys, Arg, Orn, Dab, Dap,α-DiethylGly, Glu, Phe, hLeu, Lys, Leu, Asn, Ogl, Pro, Gln, Asp, Arg,Ser, spiro-pip, Thr, Tba, Tlc, Val or Tyr, or a corresponding α-methylamino acid form of any of the foregoing; X14 is Asn, Glu, Phe, Gly, His,Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic or Tyr, Lys(Ac), Orn ora corresponding α-methyl amino acid form of any of the foregoing; X15 isGly, (D)Ala, (D)Asn, (D)Asp, Asn, (D)Leu, (D)Phe, (D)Thr, Ala, AEA, Asp,Glu, Phe, Gly, Lys, Leu, Pro, Gln, Arg or Ser, β-Ala, Arg or acorresponding α-methyl amino acid form of any of the foregoing; X16 isabsent, Gly, Ala, Asp, Ser, Pro, Asn or Thr, or a corresponding α-methylamino acid form of any of the foregoing; X17 is absent, Glu, Ser, Gly orGln, or a corresponding α-methyl amino acid form of any of theforegoing; X18 is absent or any amino acid; X19 is absent or any aminoacid; and X20 is absent or any amino acid. In particular embodiments,the bond between X4 and X9 is a disulfide bond. In certain embodiments,X1, X2, and X3 are absent. In certain embodiments, X17, X19 and X20 areabsent. In certain embodiments, one or both of X4 or X9 is Pen. Incertain embodiments, both X4 and X9 are Pen. In particular embodiments,X18 is (D)-Lys. In certain embodiments, the peptide inhibitors compriseone or more, two or more, three or more, or four of the following: X5 isArg, Asn, Gln, Dap, Orn; X6 is Thr or Ser; X7 is Trp, 2-Nal, 1-Nal,Phe(4-OAllyl), Tyr(3-tBu), Phe(4-tBu), Phe(4-guanidino), Phe(Bzl) orPhe(4-Me), 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, α-MeTrp or1,2,3,4-tetrahydro-norharman; and X8 is Gln, Val, Phe, Glu, Lys. Incertain embodiments, the peptide inhibitors comprise one or more, two ormore, three or more, four or more, five or more, six or more, or sevenof the following: X10 is Tyr, Phe(4-OBzl), Phe(4-OMe), Phe(4-CONH₂),Phe(3,4-Cl₂), Phe(4-tBu), Phe(4-NH₂), Phe(4-Br), Phe(4-CN), Phe(4-CO₂H),Phe(4-(2aminoethoxy)) or Phe(4-guanadino); X11 is Trp, 2-Nal, 1-Nal,Phe(4-OAllyl), Tyr(3-tBu), Phe(4-tBu), Phe(4-guanidino), Phe(Bzl) orPhe(4-Me), 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, α-MeTrp or1,2,3,4-tetrahydro-norharman; X12 is Arg, α-MeLys α-MeLeu, Aib orα-MeOrn; X13 is Lys, Glu or Lys(Ac); X14 is Phe or Asn; X15 is Gly, Sror Ala; and X16 is absent or AEA. In certain embodiments, X4 and X9 arePen; X5 is Gln; X6 is Thr; X7 is Trp; X8 is Gln; X10 is Tyr, Phe(4-OMe)or 2-Nal; X11 is Trp, 2-Nal or 1-Nal; X12 is Arg, αMeLys or α-MeOrn; X13is Lys, Glu or Lys(Ac); X14 is Phe or Asn; X15 is Gly; and X16 isabsent. In certain embodiments, one or more of X1, X2 and X3 are absent;and one or more, two or more, three or more, or four of X17, X18, X19and X20 are absent.

In certain embodiments of peptide inhibitors of Xa: X4 is Abu, Pen, orCys; X7 is Trp, Bip, Gln, His, Glu(Bzl), 4-Phenylbenzylalanine, Tic,Phe[4-(2-aminoethoxy)], Phe(3,4-Cl₂), Phe(4-OMe), 5-Hydroxy-Trp,6-Chloro-Trp, N-MeTrp, α-MeTrp, 1,2,3,4-tetrahydro-norharman,Phe(4-CO₂H), Phe(4-CONH₂), Phe(3,4-Dimethoxy), Phe(4-CF₃), PP-diPheAla,Phe(4-tBu), Glu, Gly, Ile, Asn, Pro, Arg, Thr or Octgly, or acorresponding α-methyl amino acid form of any of the foregoing; X9 isAbu, Pen, or Cys; X10 is 1-Nal, 2-Nal, Aic, Bip, (D)Cys, Cha, DMT,(D)Tyr, Glu, Phe, His, Trp, Thr, Tic, Tyr, 4-pyridylAla, Octgly a Pheanalog or a Tyr analog, or a corresponding α-methyl amino acid form ofany of the foregoing; X11 is 2-Nal, 1-Nal, 2,4-dimethylPhe, Bip,4-phenylcyclohexyl, Glu(Bzl), 4-Phenylbenzylalanine, Tic,Phe[4-(2-aminoethoxy)], Phe(3,4-Cl₂), Phe(3,4-F₂), βhPhe(4-F),Phe(4-OMe), 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, α-MeTrp,1,2,3,4-tetrahydro-norharman, Phe(4-CO₂H), Phe(4-CONH₂),Phe(3,4-Dimethoxy), Phe(4-CF₃), Phe(2,3-Cl₂), Phe(2,3-F₂), Phe(4-F),4-phenylcyclohexylalanine, α-MePhe, βhNal, βhPhe, βhTyr, βhTrp, Bip,Nva(5-phenyl), Phe, His, hPhe, Tqa, Trp, Tyr, Phe(4-Me),Trp(2,5,7-tri-tertButyl), Phe(4-OAllyl), Tyr(3-tBu), Phe(4-tBu),Phe(4-guanidino), Phe(4-OBzl), or Octgly, or a corresponding α-methylamino acid form of any of the foregoing; X12 is α-MeLys, α-MeOrn,α-MeLeu, MeLeu, Aib, (D)Ala, (D)Asn, (D)Leu, (D)Asp, (D)Phe, (D)Thr,3-Pal, Aib, β-Ala, βhGlu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg,Asp, Dab, Dap, α-DiethylGly, Glu, Phe, hLeu, hArg, hLeu, Ile, Lys, Leu,Asn, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Arg, Ser, Thr or Tle, or acorresponding α-methyl amino acid form of any of the foregoing; X13 isLys(Ac), (D)Asn, (D)Leu, (D)Thr, (D)Phe, Ala, Aib, α-MeLeu, βAla, βhGlu,βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Arg, Orn, Dab, Dap,α-DiethylGly, Glu, Phe, hLeu, Lys, Leu, Asn, Ogl, Pro, Gln, Asp, Arg,Ser, spiro-pip, Thr, Tba, Tlc, Val or Tyr, or a corresponding α-methylamino acid form of any of the foregoing; X14 is Asn, Glu, Phe, Gly, His,Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic or Tyr, or acorresponding α-methyl amino acid form of any of the foregoing; X15 isGly, (D)Ala, (D)Asn, (D)Asp, Asn, (D)Leu, (D)Phe, (D)Thr, Ala, AEA, Asp,Glu, Phe, Gly, Lys, Leu, Pro, Gln, Arg or Ser, or a correspondingα-methyl amino acid form of any of the foregoing, or X15 is Gly, (D)Ala,(D)Asn, (D)Asp, Asn, (D)Leu, (D)Phe, (D)Thr, Ala, Asn, Ser, AEA, Asp,Glu, Phe, Gly, Lys, Leu, Pro, Gln, Arg or Ser, or a correspondingα-methyl amino acid form of any of the foregoing; X16 is absent, Gly,Ala, Asp, Ser, Pro, Asn or Thr, or a corresponding α-methyl amino acidform of any of the foregoing; and X17 is absent, Glu, Ser, Gly or Gln,or a corresponding α-methyl amino acid form of any of the foregoing. Inparticular embodiments, the peptide inhibitor is cyclized via anintramolecular bond between X4 and X9. In certain embodiments, one ormore of X1, X2, and X3 are absent. In certain embodiments, one or moreof X17, X19 and X20 are absent. In certain embodiments, one of X4 or X9is Abu, and the other of X4 or X9 is not Abu. In certain embodiments,the peptide inhibitors comprise one or more, two or more, three or more,or four of the following: X5 is Arg, Gln, Dap or Orn; X6 is Thr or Ser;X7 is Trp, 2-Nal, 1-Nal, Phe(4-OAllyl), Tyr(3-tBu), Phe(4-tBu),Phe(4-guanidino), Phe(4-OBzl), Phe(4-Me), 5-Hydroxy-Trp, 6-Chloro-Trp,N-MeTrp, or α-MeTrp, 1,2,3,4-tetrahydro-norharman; and X8 is Gln, Val,Phe, Glu or Lys. In certain embodiments, the peptide inhibitors compriseone or more, two or more, three or more, four or more, five or more, sixor more, or seven of the following: X10 is Tyr, Phe(4-OBzl), Phe(4-OMe),Phe(4-CONH₂), Phe(3,4-Cl₂), Phe(4-tBu), Phe(4-NH₂), Phe(4-Br),Phe(4-CN), Phe(4-CO₂H), Phe(4-(2aminoethoxy)) or Phe(4-guanadino); X11is Trp, 2-Nal, 1-Nal, Phe(4-OAllyl), Tyr(3-tBu), Phe(4-tBu),Phe(4-guanidino), Phe(Bzl) or Phe(4-Me), 5-Hydroxy-Trp, 6-Chloro-Trp,N-MeTrp, α-MeTrp or 1,2,3,4-tetrahydro-norharman; X12 is Arg, hLeu,(D)Asn, Aib, α-MeLys, α-MeLeu or α-MeOrn; X13 is Lys, Glu or Lys(Ac);X14 is Phe or Asn; X15 is Gly, Ser or Ala, or X15 is Asn, Gly, Ser, βAlaor Ala; and X16 is absent or AEA.

In another aspect, the present invention includes peptide inhibitorscomprising the structure of Formula I:

R¹—X—R²  (I)

or a pharmaceutically acceptable salt or solvate thereof, wherein

R¹ is a bond, hydrogen, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12 aryl, aC1-C6 alkyl, a C1-C20 alkanoyl, and including PEGylated versions aloneor as spacers of any of the foregoing;

R² is a bond, OH or NH₂; and

X is any of the peptide sequences described herein, e.g., Xa, Ia, Ib,Ic, Id, Ie.

In a related aspect, the present invention includes a peptide dimerinhibitor of an interleukin-23 receptor, wherein the peptide dimerinhibitor comprises two peptide monomer subunits connected via one ormore linker moieties, wherein each peptide monomer subunit has asequence or structure set forth herein. In certain embodiments, one orboth peptide monomer subunit is cyclized via an intramolecular bondbetween X4 and X9. In certain embodiments, one or both intramolecularbond is a disulfide bond, a thioether bond, a lactam bond, aselenoether, diselenide, or an olefin bond. In certain embodiments, thelinker is any of those shown in Table 2. In certain embodiments, thelinker moiety is a diethylene glycol linker, an iminodiacetic acid (IDA)linker, a β-Ala-iminodiaceticacid (β-Ala-IDA) linker, or a PEG linker.In particular embodiments, the N-terminus of each peptide monomersubunit is connected by the linker moiety. In particular embodiments,the C-terminus of each peptide monomer subunit is connected by thelinker moiety. In certain embodiments, the linker connects an internalamino acid residue of at least one of the peptide monomer subunits tothe N-terminus, C-terminus, or an internal amino acid residue of theother peptide monomer subunit.

In a further related aspect, the present invention includes apolynucleotide comprising a sequence encoding a peptide inhibitor of thepresent invention or one or both peptide monomer subunit of a peptidedimer inhibitor of the present invention. The present invention alsoincluded a vector comprising the polynucleotide.

In another aspect, the present invention includes a pharmaceuticalcomposition comprising a peptide inhibitor or a peptide dimer inhibitorof the present invention, and a pharmaceutically acceptable carrier,excipient, or diluent. In particular embodiments, the pharmaceuticalcomposition comprises an enteric coating. In certain embodiments, theenteric coating protects and releases the pharmaceutical compositionwithin a subject's lower gastrointestinal system.

In another aspect, the present invention includes a method for treatingor preventing a disease associated with IL-23 signalling, including butnot limited to an Inflammatory Bowel Disease (IBD), ulcerative colitis,Crohn's disease, Celiac disease (nontropical Sprue), enteropathyassociated with seronegative arthropathies, microscopic colitis,collagenous colitis, eosinophilic gastroenteritis, colitis associatedwith radio- or chemo-therapy, colitis associated with disorders ofinnate immunity as in leukocyte adhesion deficiency-1, chronicgranulomatous disease, glycogen storage disease type 1b,Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-AldrichSyndrome, pouchitis resulting after proctocolectomy and ileoanalanastomosis, gastrointestinal cancer, pancreatitis, insulin-dependentdiabetes mellitus, mastitis, cholecystitis, cholangitis,pericholangitis, chronic bronchitis, chronic sinusitis, asthma,psoriasis, or graft versus host disease in a subject, comprisingproviding to the subject an effective amount of the pharmaceuticalcomposition of the present invention. In certain embodiments, theinflammatory bowel disease is ulcerative colitis or Crohn's disease. Inparticular embodiments, the peptide inhibitor or the peptide dimerinhibitor inhibits binding of an interleukin-23 (IL-23) to theinterleukin-23 receptor (IL-23R). In certain embodiments, thepharmaceutical composition is provided to the subject by an oral,intravenous, peritoneal, intradermal, subcutaneous, intramuscular,intrathecal, inhalation, vaporization, nebulization, sublingual, buccal,parenteral, rectal, intraocular, inhalation, vaginal, or topical routeof administration. In particular embodiments, the pharmaceuticalcomposition is provided orally for treating Inflammatory Bowel Disease(IBD), ulcerative colitis, Crohn's disease. In certain embodiments, thepharmaceutical composition is provided to the subject topically,parenterally, intravenously, subcutaneously, peritoneally, orintravenously for treating psoriasis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides an example of a rat IL-23 dose-response curve asmeasured by levels of IL-17A in the rat splenocyte assay.

FIG. 2 is a graph showing IL-12-dependent production of IFNγ from humanPBMCs treated with the indicated amounts of Compound A or Compound B.

FIGS. 3A and 3B show results for DAI values from Day 7. Statisticalanalysis for significance was determined using Student's t-test(GraphPad Prism). Differences were noted as significant *p<0.05,**p<0.01, ***p<0.001, ****p<0.0001.

FIG. 4 shows an alignment of the amino acid sequences of human IL23R(SEQ ID NO: 760), mouse IL-23R (SEQ ID NO: 761), rat IL23R (SEQ ID NO:762), chimp IL-23R (SEQ ID NO: 763), dog IL-23R (SEQ ID NO: 764) and cowIL-23R (SEQ ID NO: 765), with highly conserved amino acid residuesshaded. The region of mouse IL-23R lacking in the other IL-23R speciesshown is shown, and a region of IL23R that may be bound by certainpeptide inhibitors of the present invention is indicated by a dashedline.

FIG. 5 is a table outlining the study design for TNBS induced colitis inrats.

FIGS. 6A-6D are graphs showing colon weight to length (FIG. 6A), colonwall thickness (FIG. 6B), colon macroscopic score (FIG. 6C) ormyeloperoxidase (MPO) abundance (FIG. 6D) in proximal colon extractsquantified by ELISA, following sham treatment, vehicle treatment, ortreatment with the indicated amounts of anti-IL23p19 antibody orCompound C. Values are shown as mean±SD. Statistical significanceassessed by one-way ANOVA: *≦0.05; **≦0.01; ***p≦0.001; ****p≦0.0001;ns, not significant.

FIG. 7 provides micrographs of colon lesions found in animals followingsham treatment (upper left panel), vehicle treatment (upper right panel)showing transmural inflammation, presence of necrotic tissue, and mucosadevoid of crypts, anti-IL23p19 antibody (lower left panel), or 160mg/kg/d Compound C (lower right panel) showing restriction of lesions tothe mucosa.

FIGS. 8A-8E are graphs showing inflammation (FIG. 8A), mucosal necrosis(FIG. 8B), grand loss (FIG. 8C), colon wall thickness (FIG. 8D) andhistological score (FIG. 8E) following vehicle treatment, treatment withanti-IL23p19 antibody, or treatment with the indicated amount ofCompound C

FIGS. 9A-9C shows the concentration of Compound C in the plasma andproximal colon determined one hour post last PO dose (FIG. 9A; leftpanel), and fold above IC75 of its activity as determined by the ratsplenocyte assay (FIG. 9B; middle panel) and the rat IL23R ELISA assay(FIG. 9C; right panel).

FIG. 10 provides a schematic diagram depicting the structure of certainpeptide inhibitors and illustrating representative types of bondsbetween X4 and X9.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise defined herein, scientific and technical terms used inthis application shall have the meanings that are commonly understood bythose of ordinary skill in the art. Generally, nomenclature used inconnection with, and techniques of, chemistry, molecular biology, celland cancer biology, immunology, microbiology, pharmacology, and proteinand nucleic acid chemistry, described herein, are those well-known andcommonly used in the art.

As used herein, the following terms have the meanings ascribed to themunless specified otherwise.

Throughout this specification, the word “comprise” or variations such as“comprises” or “comprising” will be understood to imply the inclusion ofa stated integer (or components) or group of integers (or components),but not the exclusion of any other integer (or components) or group ofintegers (or components).

The singular forms “a,” “an,” and “the” include the plurals unless thecontext clearly dictates otherwise.

The term “including” is used to mean “including but not limited to.”“Including” and “including but not limited to” are used interchangeably.

The terms “patient,” “subject,” and “individual” may be usedinterchangeably and refer to either a human or a non-human animal. Theseterms include mammals such as humans, primates, livestock animals (e.g.,bovines, porcines), companion animals (e.g., canines, felines) androdents (e.g., mice and rats).

The term “peptide,” as used herein, refers broadly to a sequence of twoor more amino acids joined together by peptide bonds. It should beunderstood that this term does not connote a specific length of apolymer of amino acids, nor is it intended to imply or distinguishwhether the polypeptide is produced using recombinant techniques,chemical or enzymatic synthesis, or is naturally occurring.

The recitations “sequence identity”, “percent identity”, “percenthomology”, or, for example, comprising a “sequence 50% identical to,” asused herein, refer to the extent that sequences are identical on anucleotide-by-nucleotide basis or an amino acid-by-amino acid basis overa window of comparison. Thus, a “percentage of sequence identity” may becalculated by comparing two optimally aligned sequences over the windowof comparison, determining the number of positions at which theidentical nucleic acid base (e.g., A, T, C, G, I) or the identical aminoacid residue (e.g., Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr,Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys and Met) occurs in bothsequences to yield the number of matched positions, dividing the numberof matched positions by the total number of positions in the window ofcomparison (i.e., the window size), and multiplying the result by 100 toyield the percentage of sequence identity.

Calculations of sequence similarity or sequence identity betweensequences (the terms are used interchangeably herein) can be performedas follows. To determine the percent identity of two amino acidsequences, or of two nucleic acid sequences, the sequences can bealigned for optimal comparison purposes (e.g., gaps can be introduced inone or both of a first and a second amino acid or nucleic acid sequencefor optimal alignment and non-homologous sequences can be disregardedfor comparison purposes). In certain embodiments, the length of areference sequence aligned for comparison purposes is at least 30%,preferably at least 40%, more preferably at least 50%, 60%, and evenmore preferably at least 70%, 80%, 90%, 100% of the length of thereference sequence. The amino acid residues or nucleotides atcorresponding amino acid positions or nucleotide positions are thencompared. When a position in the first sequence is occupied by the sameamino acid residue or nucleotide as the corresponding position in thesecond sequence, then the molecules are identical at that position.

The percent identity between the two sequences is a function of thenumber of identical positions shared by the sequences, taking intoaccount the number of gaps, and the length of each gap, which need to beintroduced for optimal alignment of the two sequences.

The comparison of sequences and determination of percent identitybetween two sequences can be accomplished using a mathematicalalgorithm. In some embodiments, the percent identity between two aminoacid sequences is determined using the Needleman and Wunsch, (1970, J.Mol. Biol. 48: 444-453) algorithm which has been incorporated into theGAP program in the GCG software package, using either a Blossum 62matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferredembodiment, the percent identity between two nucleotide sequences isdetermined using the GAP program in the GCG software package, using anNWSgapdna. CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and alength weight of 1, 2, 3, 4, 5, or 6. Another exemplary set ofparameters includes a Blossum 62 scoring matrix with a gap penalty of12, a gap extend penalty of 4, and a frameshift gap penalty of 5. Thepercent identity between two amino acid or nucleotide sequences can alsobe determined using the algorithm of E. Meyers and W. Miller (1989,Cabios, 4: 11-17) which has been incorporated into the ALIGN program(version 2.0), using a PAM120 weight residue table, a gap length penaltyof 12 and a gap penalty of 4.

The peptide sequences described herein can be used as a “query sequence”to perform a search against public databases to, for example, identifyother family members or related sequences. Such searches can beperformed using the NBLAST and XBLAST programs (version 2.0) ofAltschul, et al., (1990, J. Mol. Biol, 215: 403-10). BLAST nucleotidesearches can be performed with the NBLAST program, score=100,wordlength=12 to obtain nucleotide sequences homologous to nucleic acidmolecules of the invention. BLAST protein searches can be performed withthe XBLAST program, score=50, wordlength=3 to obtain amino acidsequences homologous to protein molecules of the invention. To obtaingapped alignments for comparison purposes, Gapped BLAST can be utilizedas described in Altschul et al. (Nucleic Acids Res. 25:3389-3402, 1997).When utilizing BLAST and Gapped BLAST programs, the default parametersof the respective programs (e.g., XBLAST and NBLAST) can be used.

The term “conservative substitution” as used herein denotes that one ormore amino acids are replaced by another, biologically similar residue.Examples include substitution of amino acid residues with similarcharacteristics, e.g., small amino acids, acidic amino acids, polaramino acids, basic amino acids, hydrophobic amino acids and aromaticamino acids. See, for example, the table below. In some embodiments ofthe invention, one or more Met residues are substituted with norleucine(Nle) which is a bioisostere for Met, but which, as opposed to Met, isnot readily oxidized. Another example of a conservative substitutionwith a residue normally not found in endogenous, mammalian peptides andproteins is the conservative substitution of Arg or Lys with, forexample, ornithine, canavanine, aminoethylcysteine or another basicamino acid. In some embodiments, one or more cysteines of a peptideanalogue of the invention may be substituted with another residue, suchas a serine. For further information concerning phenotypically silentsubstitutions in peptides and proteins, see, for example, Bowie et. al.Science 247, 1306-1310, 1990. In the scheme below, conservativesubstitutions of amino acids are grouped by physicochemical properties.I: neutral, hydrophilic, II: acids and amides, III: basic, IV:hydrophobic, V: aromatic, bulky amino acids.

I II III IV V A N H M F S D R L Y T E K I W P Q V G C

In the scheme below, conservative substitutions of amino acids aregrouped by physicochemical properties. VI: neutral or hydrophobic, VII:acidic, VIII: basic, IX: polar, X: aromatic.

VI VII VIII IX X A E H M F L D R S Y I K T W P C G N V Q

The term “amino acid” or “any amino acid” as used here refers to any andall amino acids, including naturally occurring amino acids (e.g.,a-amino acids), unnatural amino acids, modified amino acids, andnon-natural amino acids. It includes both D- and L-amino acids. Naturalamino acids include those found in nature, such as, e.g., the 23 aminoacids that combine into peptide chains to form the building-blocks of avast array of proteins. These are primarily L stereoisomers, although afew D-amino acids occur in bacterial envelopes and some antibiotics. The20 “standard,” natural amino acids are listed in the above tables. The“non-standard,” natural amino acids are pyrrolysine (found inmethanogenic organisms and other eukaryotes), selenocysteine (present inmany noneukaryotes as well as most eukaryotes), and N-formylmethionine(encoded by the start codon AUG in bacteria, mitochondria andchloroplasts). “Unnatural” or “non-natural” amino acids arenon-proteinogenic amino acids (i.e., those not naturally encoded orfound in the genetic code) that either occur naturally or are chemicallysynthesized. Over 140 unnatural amino acids are known and thousands ofmore combinations are possible. Examples of “unnatural” amino acidsinclude β-amino acids (β³ and β²), homo-amino acids, proline and pyruvicacid derivatives, 3-substituted alanine derivatives, glycinederivatives, ring-substituted phenylalanine and tyrosine derivatives,linear core amino acids, diamino acids, D-amino acids, alpha-methylamino acids and N-methyl amino acids. Unnatural or non-natural aminoacids also include modified amino acids. “Modified” amino acids includeamino acids (e.g., natural amino acids) that have been chemicallymodified to include a group, groups, or chemical moiety not naturallypresent on the amino acid. According to certain embodiments, a peptideinhibitor comprises an intramolecular bond between two amino acidresidues present in the peptide inhibitor. It is understood that theamino acid residues that form the bond will be altered somewhat whenbonded to each other as compared to when not bonded to each other.Reference to a particular amino acid is meant to encompass that aminoacid in both its unbonded and bonded state. For example, the amino acidresidue homoSerine (hSer) or homoSerine(Cl) in its unbonded form maytake the form of 2-aminobutyric acid (Abu) when participating in anintramolecular bond according to the present invention. The presentinvention includes both peptide inhibitors containing cross-linksbetween X4 and X9, as well as the peptide inhibitors that do not containcross-links between X4 and X9, e.g., before cross-link formation. Assuch, the names hSer and Abu are intended to indicate the same aminoacids and are used interchangeably.

For the most part, the names of naturally occurring and non-naturallyoccurring aminoacyl residues used herein follow the naming conventionssuggested by the IUPAC Commission on the Nomenclature of OrganicChemistry and the IUPAC-IUB Commission on Biochemical Nomenclature asset out in “Nomenclature of α-Amino Acids (Recommendations, 1974)”Biochemistry, 14(2), (1975). To the extent that the names andabbreviations of amino acids and aminoacyl residues employed in thisspecification and appended claims differ from those suggestions, theywill be made clear to the reader. Some abbreviations useful indescribing the invention are defined below in the following Table 1A.

TABLE 1A Abbreviations of Non-Natural Amino Acids and Chemical Moieties(for amino acid derivatives, all L unless stated) AbbreviationDefinition Ac- Acetyl Hy Hydrogen (Free N-terminal) DapL-Diaminopropionic acid Dab L-Diaminobutyric acid Orn L-Ornathine PenL-Penicillamine Sarc Sarcosine Cit L-Citrulline Cav L-CavaninePhe-(4-Guanidino) 4-Guanidine-L-Phenylalanine N-MeArgN-Methyl-L-Arginine N-MeTrp N-Methyl-L-Tryptophan N-MeGlnN-Methyl-L-Glutamine N-MeAla N-Methyl-L-Alanine N-MeLys N-Methyl-LysineN-MeAsn N-Methyl-L-Asparagine 6-ChloroTrp 6-Chloro-L-Tryptophan5-HydroxyTrp 5-Hydroxy-L-Tryptophan 1,2,3,4-tetrahydro-L-1,2,3,4-tetrahydro-norharman norharman 2-Nal L-2-Napthylalanine (alsoreferred to as 2-Nap) 1-Nal L-1-Napthylalanine (also referred to as1-Nap) Phe(4-OMe) 4-Methoxy-L-phenylalanine Abu 2-Aminobutyric acid BipL-4,4′-Biphenylalanine βAla beta-Alanine βhTyr beta homo-L-TyrosineβhTrp beta homo-L-Trptophan βhAla beta homo-L-Alanine βhLeu, betahomo-L-Leucine βhVal beta homo-L-Valine Aib 2-aminoisobutyric acid AztL-azetidine-2-carboxylic acid Tic (3S)-1,2,3,4-Tetrahydroisoquinoline-7-hydroxy-3-carboxylic Acid Phe(4-OMe) 4-methoxy-L-phenylalanineN-Me-Lys N-Methyl-L-Lysine N-Me-Lys(Ac) N-ε-Acetyl-D-lysine CONH₂Carboxamide COOH Acid 3-Pal L-3-Pyridylalanine Phe(4-F)4-Fluoro-L-Phenylalanine DMT 2,6-DimethylTyrosine Phe(4-OMe)4-Methoxyphenylalanine hLeu L-homoLeucine hArg L-homoArginine α-MeLysalpha-methyl-L-Lysine α-MeOrn alpha-methyl-L-Ornathine α-MeLeualpha-methyl-L-Leucine α-MeTrp alpha-methyl-L-Tryptophan α-MePhealpha-methyl-L-Phenylalanine α-MeTyr alpha-methyl-L-Tyrosineα-DiethylGly α-DiethylGlycine Lys(Ac) N-ε-acetyl-L-Lysine DTTDithiothreotol Nle L-Norleucine βhTrp L-β-homoTrypophan βhPheL-β-homophenylalanine βhPro L-β-homoproline Phe(4-CF₃)4-Trifluoromethyl-L-Phenylalanine β-Glu L-β-Glutamic acid βhGluL-β-homoglutamic acid 2-2-Indane 2-Aminoindane-2-carboxylic acid1-1-Indane 1-Aminoindane-1-carboxylic acid hCha L-homocyclohexylalanineCyclobutyl L-cyclobutylalanine βhPhe L-β-homo-phenylalanine GlaGama-Carboxy-L-Glutamic acid Cpa Cyclopentyl-L-alanine ChaCyclohexyl-L-alanine Octgly L-Octylglycine t-butyl-Ala3-(tert-butyl)-L-A1a-OH t-butyl-Gly tert-butyl-glycine AEP3-(2-aminoethoxy)propanoic acid AEA (2-aminoethoxy)acetic acidPhe(4-Phenoxy)] 4-Phenoxy-L-phenylalanine Phe(4-OBzl)O-Benzyl-L-tyrosine Phe(4-CONH₂) 4-Carbamoyl-L-phenylalanine Phe(4-CO₂H)4-Carboxy-L-phenylalanine Phe(3,4-Cl₂) 3,4 dichloro-L-phenylalanineTyr(3-t-Bu) 3-t-butyl-L-tyrosine Phe(t-Bu) t-butyl-L-phenylalaninePhe[4-(2-aminoethoxy)]

Phe(4-CN) 4-cyano-L-phenylalanine Phe(4-Br) 4-bromo-L-phenylalaninePhe(4-NH₂) 4-amino-L-phenylalanine Phe(4-Me) 4-methyl-L-phenylalanine4-Pyridylalanine 4-L-Pyridylalanine 4-amino-4- carboxy-piperidine

hPhe(3,4-dimethoxy) 3,4-dimethoxy-L-homophenylalanine Phe(2,4-Me₂)2,4-dimethyl-L-phenylalanine Phe(3,5-F₂) 3,5-difluoro-L-phenylalaninePhe(penta-F) pentafluoro-L-phenylalanine 2,5,7-tert butyl Trp2,5,7-Tris-tert-butyl-L-tryptophan Tic

Phe(4-OAllyl) O-Allyl-L-Tyrosine Phe(4-N₃) 4-azidophenylalanine Achc

Acvc

Acbc

Acpc

4-amino-4-carboxy- tetrahydropyran (also referred as THP)

Throughout the present specification, unless naturally occurring aminoacids are referred to by their full name (e.g. alanine, arginine, etc.),they are designated by their conventional three-letter or single-letterabbreviations (e.g. Ala or A for alanine, Arg or R for arginine, etc.).Unless otherwise indicated, three-letter and single-letter abbreviationsof amino acids refer to the L-isomeric form of the amino acid inquestion. The term “L-amino acid,” as used herein, refers to the “L”isomeric form of a peptide, and conversely the term “D-amino acid”refers to the “D” isomeric form of a peptide (e.g., Dasp, (D)Asp orD-Asp; Dphe, (D)Phe or D-Phe). Amino acid residues in the D isomericform can be substituted for any L-amino acid residue, as long as thedesired function is retained by the peptide. D-amino acids may beindicated as customary in lower case when referred to usingsingle-letter abbreviations.

In the case of less common or non-naturally occurring amino acids,unless they are referred to by their full name (e.g. sarcosine,ornithine, etc.), frequently employed three- or four-character codes areemployed for residues thereof, including, Sar or Sarc (sarcosine, i.e.N-methylglycine), Aib (α-aminoisobutyric acid), Dab (2,4-diaminobutanoicacid), Dapa (2,3-diaminopropanoic acid), γ-Glu (γ-glutamic acid), Gaba(γ-aminobutanoic acid), β-Pro (pyrrolidine-3-carboxylic acid), and 8Ado(8-amino-3,6-dioxaoctanoic acid), Abu (2-amino butyric acid), βhPro(β-homoproline), βhPhe (β-homophenylalanine) and Bip (β,βdiphenylalanine), and Ida (Iminodiacetic acid).

As is clear to the skilled artisan, the peptide sequences disclosedherein are shown proceeding from left to right, with the left end of thesequence being the N-terminus of the peptide and the right end of thesequence being the C-terminus of the peptide. Among sequences disclosedherein are sequences incorporating a “Hy-” moiety at the amino terminus(N-terminus) of the sequence, and either an “—OH” moiety or an “—NH₂”moiety at the carboxy terminus (C-terminus) of the sequence. In suchcases, and unless otherwise indicated, a “Hy-” moiety at the N-terminusof the sequence in question indicates a hydrogen atom, corresponding tothe presence of a free primary or secondary amino group at theN-terminus, while an “—OH” or an “—NH₂” moiety at the C-terminus of thesequence indicates a hydroxy group or an amino group, corresponding tothe presence of an amido (CONH₂) group at the C-terminus, respectively.In each sequence of the invention, a C-terminal “—OH” moiety may besubstituted for a C-terminal “—NH₂” moiety, and vice-versa.

The term “DRP,” as used herein, refers to disulfide rich peptides.

The term “dimer,” as used herein, refers broadly to a peptide comprisingtwo or more monomer subunits. Certain dimers comprise two DRPs. Dimersof the present invention include homodimers and heterodimers. A monomersubunit of a dimer may be linked at its C- or N-terminus, or it may belinked via internal amino acid residues. Each monomer subunit of a dimermay be linked through the same site, or each may be linked through adifferent site (e.g., C-terminus, N-terminus, or internal site).

The term “NH₂,” as used herein, refers to a free amino group present atthe amino terminus of a polypeptide. The term “OH,” as used herein,refers to a free carboxy group present at the carboxy terminus of apeptide. Further, the term “Ac,” as used herein, refers to Acetylprotection through acylation of the C- or N-terminus of a polypeptide.

The term “carboxy,” as used herein, refers to —CO₂H.

The term “isostere replacement,” as used herein, refers to any aminoacid or other analog moiety having chemical and/or structural propertiessimilar to a specified amino acid.

The term “cyclized,” as used herein, refers to a reaction in which onepart of a polypeptide molecule becomes linked to another part of thepolypeptide molecule to form a closed ring, such as by forming adisulfide bridge or other similar bond.

The term “subunit,” as used herein, refers to one of a pair ofpolypeptide monomers that are joined to form a dimer peptidecomposition.

The term “linker moiety,” as used herein, refers broadly to a chemicalstructure that is capable of linking or joining together two peptidemonomer subunits to form a dimer.

The term “pharmaceutically acceptable salt,” as used herein, representssalts or zwitterionic forms of the peptides or compounds of the presentinvention which are water or oil-soluble or dispersible, which aresuitable for treatment of diseases without undue toxicity, irritation,and allergic response; which are commensurate with a reasonablebenefit/risk ratio, and which are effective for their intended use. Thesalts can be prepared during the final isolation and purification of thecompounds or separately by reacting an amino group with a suitable acid.Representative acid addition salts include acetate, adipate, alginate,citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,camphorate, camphorsulfonate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate),lactate, maleate, mesitylenesulfonate, methanesulfonate,naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate,propionate, succinate, tartrate, trichloroacetate, trifluoroacetate,phosphate, glutamate, bicarbonate, para-toluenesulfonate, andundecanoate. Also, amino groups in the compounds of the presentinvention can be quaternized with methyl, ethyl, propyl, and butylchlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamylsulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, andiodides; and benzyl and phenethyl bromides. Examples of acids which canbe employed to form therapeutically acceptable addition salts includeinorganic acids such as hydrochloric, hydrobromic, sulfuric, andphosphoric, and organic acids such as oxalic, maleic, succinic, andcitric. A pharmaceutically acceptable salt may suitably be a saltchosen, e.g., among acid addition salts and basic salts. Examples ofacid addition salts include chloride salts, citrate salts and acetatesalts. Examples of basic salts include salts where the cation isselected among alkali metal cations, such as sodium or potassium ions,alkaline earth metal cations, such as calcium or magnesium ions, as wellas substituted ammonium ions, such as ions of the typeN(R1)(R2)(R3)(R4)+, where R1, R2, R3 and R4 independently will typicallydesignate hydrogen, optionally substituted C1-6-alkyl or optionallysubstituted C2-6-alkenyl. Examples of relevant C1-6-alkyl groups includemethyl, ethyl, 1-propyl and 2-propyl groups. Examples of C2-6-alkenylgroups of possible relevance include ethenyl, 1-propenyl and 2-propenyl.Other examples of pharmaceutically acceptable salts are described in“Remington's Pharmaceutical Sciences”, 17th edition, Alfonso R. Gennaro(Ed.), Mark Publishing Company, Easton, Pa., USA, 1985 (and more recenteditions thereof), in the “Encyclopaedia of Pharmaceutical Technology”,3rd edition, James Swarbrick (Ed.), Informa Healthcare USA (Inc.), NY,USA, 2007, and in J. Pharm. Sci. 66: 2 (1977). Also, for a review onsuitable salts, see Handbook of Pharmaceutical Salts: Properties,Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Othersuitable base salts are formed from bases which form non-toxic salts.Representative examples include the aluminum, arginine, benzathine,calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium,meglumine, olamine, potassium, sodium, tromethamine, and zinc salts.Hemisalts of acids and bases may also be formed, e.g., hemisulphate andhemicalcium salts.

The term “N(alpha)Methylation”, as used herein, describes themethylation of the alpha amine of an amino acid, also generally termedas an N-methylation.

The term “sym methylation” or “Arg-Me-sym”, as used herein, describesthe symmetrical methylation of the two nitrogens of the guanidine groupof arginine. Further, the term “asym methylation” or “Arg-Me-asym”describes the methylation of a single nitrogen of the guanidine group ofarginine.

The term “acylating organic compounds”, as used herein refers to variouscompounds with carboxylic acid functionality that are used to acylatethe N-terminus of an amino acid or a monomer or dimer, e.g., a monomersubunit prior to forming a C-terminal dimer. Non-limiting examples ofacylating organic compounds include cyclopropylacetic acid,4-Fluorobenzoic acid, 4-fluorophenylacetic acid, 3-Phenylpropionic acid,Succinic acid, Glutaric acid, Cyclopentane carboxylic acid,3,3,3-trifluoropropeonic acid, 3-Fluoromethylbutyric acid,Tetrahedro-2H-Pyran-4-carboxylic acid.

The term “alkyl” includes a straight chain or branched, noncyclic orcyclic, saturated aliphatic hydrocarbon containing from 1 to 24 carbonatoms. Representative saturated straight chain alkyls include, but arenot limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, andthe like, while saturated branched alkyls include, without limitation,isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like.Representative saturated cyclic alkyls include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, whileunsaturated cyclic alkyls include, without limitation, cyclopentenyl,cyclohexenyl, and the like.

The term “mammal” refers to any mammalian species such as a human,mouse, rat, dog, cat, hamster, guinea pig, rabbit, livestock, and thelike.

As used herein, a “therapeutically effective amount” of the peptideinhibitor of the invention is meant to describe a sufficient amount ofthe peptide inhibitor to treat an IL-23/IL-23R-related disease,including but not limited to any of the diseases and disorders describedherein (for example, to reduce inflammation associated with IBD). Inparticular embodiments, the therapeutically effective amount willachieve a desired benefit/risk ratio applicable to any medicaltreatment.

An “analog” of an amino acid, e.g., a “Phe analog” or a “Tyr analog”means an analog of the referenced amino acid. A variety of amino acidanalogs are known and available in the art, including Phe and Tyranalogs. In certain embodiments, an amino acid analog, e.g., a Pheanalog or a Tyr analog comprises one, two, three, four or fivesubstitutions as compared to Phe or Tyr, respectively. In certainembodiments, the substitutions are present in the side chains of theamino acids. In certain embodiments, a Phe analog has the structurePhe(R²), wherein R² is a Hy, OH, CH₃, CO₂H, CONH₂, CONH₂OCH₂CH₂NH₂,t-Bu, OCH₂CH₂NH₂, phenoxy, OCH₃, OAllyl, Br, Cl, F, NH₂, N₃, orguanadino. In certain embodiments, R² is CONH₂OCH₂CH₂NH₂, OCH₃, CONH₂,OCH₃ or CO₂H. Examples of Phe analogs include, but are not limited to:hPhe, Phe(4-OMe), α-Me-Phe, hPhe(3,4-dimethoxy), Phe(4-CONH₂),Phe(4-phenoxy), Phe(4-guanadino), Phe(4-tBu), Phe(4-CN), Phe(4-Br),Phe(4-OBzl), Phe(4-NH₂), BhPhe(4-F), Phe(4-F), Phe(3,5 DiF),Phe(CH₂CO₂H), Phe(penta-F), Phe(3,4-Cl₂), Phe (3,4-F₂), Phe(4-CF₃),ββ-diPheAla, Phe(4-N₃), Phe[4-(2-aminoethoxy)], 4-Phenylbenzylalanine,Phe(4-CONH₂), Phe(3,4-Dimethoxy), Phe(4-CF₃), Phe(2,3-Cl₂), andPhe(2,3-F₂). Examples of Tyr analogs include, but are not limited to:hTyr, N-Me-Tyr, Tyr(3-tBu), Tyr(4-N₃) and βhTyr.

Peptide Inhibitors of IL-23R

Genome-wide association studies (GWAS) have demonstrated significantassociation of the IL-23 receptor (IL-23R) gene with inflammatory boweldisease (IBD), suggesting that perturbation of IL-23 signaling could berelevant to the pathogenesis of the disease. The present inventionprovides compositions and methods to modulate the IL-23 pathway throughselective antagonism of IL-23R by oral treatment with peptides that arestable and restricted to the gastrointestinal (GI) tissue. Novelinhibitory peptides that are uniquely resistant to oxidative/reductiveconditions and proteolytic degradation in a variety of assays that mimicthe various compartments of the GI environment were identified.Functionally, these peptides potently neutralize IL-23-mediatedsignaling in a transformed human cell line and in human primary cells.The binding of IL-23R is selective, since the peptides do not block theinteraction between IL-6 to IL-6R or antagonize the IL-12 signalingpathway. Furthermore, these orally delivered peptides are efficacious inattenuating colitis in a 2,4,6-trinitrobenzenesulfonic acid(TNBS)-induced acute rat model of IBD, as shown by a significantreduction in the ratio of colon weight to length, colon macroscopicscore, neutrophil infiltration, and histopathology comparable to that ofthe control anti-IL-23p19 mAb.

The present invention relates generally to peptides that have IL-23Rantagonist activity, including both peptide monomers and peptide dimers.In certain embodiments, this invention demonstrates a new paradigm fortreatment of IBD and other diseases and disorders by oral delivery ofantagonists of IL-23. IBD represents a local inflammation of theintestinal tissue; therefore, advantageous therapeutic agents would actfrom the luminal side of the intestine, yielding high drugconcentrations in diseased tissue, minimizing systemic availability andresulting in improved efficacy and safety when compared to systemicapproaches. Oral administration of the compounds of the presentinvention is expected to maximize drug levels in diseased intestinaltissues while limiting drug concentrations in circulation, therebyproviding efficacious, safe, and durable delivery for life-longtreatment of IBD and other diseases and disorders.

In certain embodiments, the present invention relates to variouspeptides, or peptide dimers comprising hetero- or homo-monomer subunits,that form cyclized structures through disulfide or other bonds. Incertain embodiments, the disulfide or other bonds are intramolecularbonds. The cyclized structure of the peptide monomer inhibitors and themonomer subunits of the peptide dimer inhibitors has been shown toincrease potency and selectivity of the peptide inhibitors. In certainembodiments, a peptide dimer inhibitor may include one or moreintermolecular bonds linking the two monomer peptide subunits within thepeptide dimer inhibitor, e.g., an intermolecular bridge between twocysteine residues, one in each peptide monomer subunit.

The present invention provides peptide inhibitors that bind to IL-23R,which may be monomers or dimers. In particular embodiments, the peptideinhibitors inhibit the binding of IL-23 to IL-23R. In certainembodiments, the IL-23R is human IL-23R, and the IL-23 is human IL-23.In certain embodiments, a peptide inhibitor of the present inventionreduces IL-23 binding to IL-23R by at least 20%, at least 30%, at least40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least90% as compared to a negative control peptide. Methods of determiningbinding are known in the art and include ELISA assays, as described inthe accompanying Examples.

In certain embodiments, a peptide inhibitor of the present invention hasan IC50 of >1 mM, <1 mM, 500 nM to 1000 nM, <500 nM, <250 nM, <100 nM,<50 nM, <25 nM, <10 nM, or <5 mM, e.g., for inhibiting binding of IL-23to IL-23R (e.g., human IL-23 and human IL-23R). Methods of determiningactivity are known in the art and include any of those described in theaccompanying Examples.

In certain embodiments, a peptide inhibitor of the present invention hasincreased stability, increased gastrointestinal stability, or increasedstability in stimulated intestinal fluid (SIF) or simulated gastricfluid (SGF), and/or under redox conditions (e.g., DTT) as compared to acontrol peptide. In certain embodiments, a control peptide is anunrelated peptide of the same or similar length. In particularembodiments, a control peptide is a peptide having the identical or ahighly related amino acid sequence (e.g., >90% sequence identity) as thepeptide inhibitor. In particular embodiments, a control peptide is apeptide having the identical or a highly related amino acid sequence(e.g., >90% sequence identity) as the peptide inhibitor, but which doesnot have a cyclized structure, e.g., through an intramolecular bondbetween two amino acid residues within the control peptide, or which isnot dimerized, or which does not comprise a conjugate for stabilization.In particular embodiments, the only difference between the peptideinhibitor and the control peptide is that the peptide inhibitorcomprises one or more amino acid substitutions that introduce one ormore amino acid residues into the peptide inhibitor, wherein theintroduced amino residue(s) forms an intrasulfide disulfide or thioetherbond with another amino acid residue in the peptide inhibitor. Oneexample of a control for a peptide dimer inhibitor is a monomer havingthe same sequence as one of the monomer subunits present in the peptidedimer inhibitor. One example of a control for a peptide inhibitorcomprising a conjugate is a peptide having the same sequence but notincluding the conjugated moiety. In certain embodiments, a controlpeptide is a peptide (e.g., a naturally-occurring peptide) correspondingto a region of IL-23 that binds to IL-23R.

Methods of determining the stability of a peptide are known in the art.In certain embodiments, the stability of a peptide inhibitor isdetermined using an SIF assay, e.g., as described in Example 3. Incertain embodiments, the stability of a peptide inhibitor is determinedusing an SGF assay, e.g., as described in Example 3. In particularembodiments, a peptide inhibitor has a half-life (e.g., in SIF or SGF orDTT) under a given set of conditions (e.g., temperature) of greater than1 minute, greater than 10 minutes, greater than 20 minutes, greater than30 minutes, greater than 60 minutes, greater than 90 minutes, greaterthan 120 minutes, greater than 3 hours, or greater than four hours whenexposed to SIF or SGF or DTT. In certain embodiments, the temperature isabout 25° C., about 4° C., or about 37° C., and the pH is aphysiological pH, or a pH about 7.4.

In some embodiments, the half-life is measured in vitro using anysuitable method known in the art, e.g., in some embodiments, thestability of a peptide of the present invention is determined byincubating the peptide with pre-warmed human serum (Sigma) at 37° C.Samples are taken at various time points, typically up to 24 hours, andthe stability of the sample is analyzed by separating the peptide orpeptide dimer from the serum proteins and then analyzing for thepresence of the peptide or peptide dimer of interest using LC-MS.

In some embodiments, a peptide inhibitor of the present inventionexhibits improved solubility or improved aggregation characteristics ascompared to a control peptide. Solubility may be determined via anysuitable method known in the art. In some embodiments, suitable methodsknown in the art for determining solubility include incubating peptidesin various buffers (Acetate pH4.0, Acetate pH5.0, Phos/Citrate pH5.0,Phos Citrate pH6.0, Phos pH 6.0, Phos pH 7.0, Phos pH7.5, Strong PBS pH7.5, Tris pH7.5, Tris pH 8.0, Glycine pH 9.0, Water, Acetic acid (pH 5.0and other known in the art) and testing for aggregation or solubilityusing standard techniques. These include, but are not limited to, visualprecipitation, dynamic light scattering, Circular Dichroism andfluorescent dyes to measure surface hydrophobicity, and detectaggregation or fibrillation, for example. In some embodiments, improvedsolubility means the peptide is more soluble in a given liquid than is acontrol peptide. In some embodiments, improved aggregation means thepeptide has less aggregation in a given liquid under a given set ofconditions than a control peptide.

In certain embodiments advantageous for achieving high compoundconcentrations in intestinal tissues when delivered orally, peptideinhibitors of the present invention are stable in the gastrointestinal(GI) environment. Proteolytic metabolism in the GI tract is driven byenzymes (including pepsins, trypsin, chymotrypsin, elastase,aminopeptidases, and carboxypeptidase AB) that are secreted from thepancreas into the lumen or are produced as brush border enzymes.Proteases typically cleave peptides and proteins that are in an extendedconformation. In the reducing environment of intestinal fluids,disulfide bonds may be broken, resulting in a linear peptide and rapidproteolysis. This luminal redox environment is largely determined by theCys/CySS redox cycle. In enterocytes, relevant activities includenumerous digestive enzymes such as CYP450 andUDP-glucuronsyl-transferase. Finally, bacteria, present in the largeintestine at concentration ranging from 10¹⁰ to 10¹² CFU/ml, constituteanother metabolic barrier. In certain embodiments, the peptideinhibitors are stable to various pHs that range from strongly acidic inthe stomach (pH 1.5-1.9), trending towards basic in the small intestine(pH 6-7.5), and then weakly acidic in the colon (pH 5-7). Such peptideinhibitors are stable during their transit through the various GIcompartments, a process that has been estimated to take 3-4 h in theintestine and 6-48 h in the colon.

In some embodiments, the peptide inhibitors of the present inventionhave less degradation, e.g., over a period of time (i.e., moredegradation stability), e.g., greater than or about 10% less, greaterthan or about 20% less, greater than or about 30% less, greater than orabout 40 less, or greater than or about 50% less degradation than acontrol peptide. In some embodiments, degradation stability isdetermined via any suitable method known in the art. In someembodiments, the degradation is enzymatic degradation. For example, incertain embodiments, the peptide inhibitors have reduced susceptibilityto degradation by trypsin, chhrmotrypsin or elastase. In someembodiments, suitable methods known in the art for determiningdegradation stability include the method described in Hawe et al., JPharm Sci, VOL. 101, No. 3, 2012, p 895-913, incorporated herein in itsentirety. Such methods are in some embodiments used to select potentpeptide sequences with enhanced shelf lifes. In particular embodiments,peptide stability is determined using a SIF assay or SGF assay asdescribed herein.

In certain embodiments, peptide inhibitors of the present inventioninhibit or reduce IL-23-mediated inflammation. In related embodiments,peptide inhibitors of the present invention inhibit or reduceIL-23-mediated secretion of one or more cytokines, e.g., by binding toIL-23R on the cell surface, thus inhibiting IL-23 binding to the cell.In particular embodiments, peptide inhibitors of the present inventioninhibit or reduce IL-23-mediated activation of Jak2, Tyk2, Stat1, Stat3,Stat4, or Stat5. Methods of determining inhibition of cytokine secretionand inhibition of signaling molecules are known in the art. For example,inhibition of IL-23/IL-23R signaling may be determined by measuringinhibition of phospho-Stat3 levels in cell lysates, as described in theaccompanying Examples, including Example 2.

In certain embodiments, peptide inhibitors of the present inventioninhibit or reduce IL-23-mediated inflammation. In related embodiments,peptide inhibitors of the present invention inhibit or reduceIL-23-mediated secretion of one or more cytokines, e.g., by binding toIL-23R on the cell surface, thus inhibiting IL-23 binding to the cell.In particular embodiments, peptide inhibitors of the present inventioninhibit or reduce IL-23-mediated activation of Jak2, Tyk2, Stat1, Stat3,Stat4, or Stat5. Methods of determining inhibition of cytokine secretionand inhibition of signaling molecules are known in the art. For example,inhibition of IL-23/IL-23R signaling may be determined by measuringinhibition of phospho-Stat3 levels in cell lysates, as described in theaccompanying Examples, including Example 2.

In certain embodiments, peptide inhibitors have increased redoxstability as compared to a control peptide. A variety of assays that maybe used to determine redox stability are known and available in the art.Any of these may be used to determine the redox stability of peptideinhibitors of the present invention.

In certain embodiments, the present invention provides various peptideinhibitors that bind or associate with the IL-23R, in vitro or in vivo,to disrupt or block binding between IL-23 and IL-23R. In certainembodiments, the peptide inhibitors bind and/or inhibit human IL-23R. Incertain embodiments, the peptide inhibitors bind and/or inhibit bothhuman and rodent IL-23R. In certain embodiments, the peptide inhibitorsbind and/or inhibit both human and rat IL-23R. In particularembodiments, the peptide inhibitors inhibit rat IL-23R at least 50%, atleast 60%, at least 70%, at least 80%, at least 90%, or at least 95% aswell as they bind or inhibit human IL-23R, e.g., as determined by anassay described herein. In certain embodiments, the peptide inhibitorspreferentially bind and/or inhibit human and/or rat IL-23R as comparedto mouse IL-23R. In particular embodiments, the peptide inhibitorspreferentially bind to rat IL-23R as compared to mouse IL-23R. Inparticular embodiments, the peptide inhibitors preferentially bind tohuman IL-23R as compared to mouse IL-23R. In certain embodiments,binding of a peptide inhibitor to mouse IL-23R is less than 75%, lessthan 50%, less than 40%, less than 30%, less than 20%, or less than 10%of binding of the same peptide inhibitor to human IL-23R and/or ratIL-23R. In certain embodiments of peptide inhibitors that preferentiallybind and/or inhibit human IL-23R and/or rat IL-23R as compared to mouseIL-23R, the peptide inhibitor binds to a region of IL-23R that isdisrupted by the presence of additional amino acids present in mouseIL-23R but not human IL-23R or rat IL-23. In one embodiment, theadditional amino acids present in the mouse IL-23R are in the regioncorresponding to about amino acid residue 315 to about amino acidresidue 340 of the mouse IL23R protein, e.g., amino acid regionNWQPWSSPFVHQTSQETGKR (SEQ ID NO: 261). In particular embodiments, thepeptide inhibitors bind to a region of human IL-23R from about aminoacid 230 to about amino acid residue 370.

In certain embodiments, peptide inhibitors show GI-restrictedlocalization following oral administration. In particular embodiments,greater than 50%, greater than 60%, greater than 70%, greater than 80%,or greater than 90% of orally administered peptide inhibitor islocalized to gastrointestinal organs and tissues. In particularembodiments, blood plasma levels of orally administered peptideinhibitor are less than 20%, less than 10%, less than 5%, less than 2%,less than 1% or less than 0.5% the levels of peptide inhibitor found inthe small intestine mucosa, colon mucosa, or proximal colon.

The various peptide inhibitors of the invention may be constructedsolely of natural amino acids. Alternatively, the peptide inhibitors mayinclude non-natural amino acids including, but not limited to, modifiedamino acids. In certain embodiments, modified amino acids includenatural amino acids that have been chemically modified to include agroup, groups, or chemical moiety not naturally present on the aminoacid. The peptide inhibitors of the invention may additionally includeone or more D-amino acids. Still further, the peptide inhibitors of theinvention may include amino acid analogs.

In certain embodiments, peptide inhibitors of the present inventioninclude one or more modified or unnatural amino acids. For example, incertain embodiments, a peptide inhibitor includes one or more of Dab,Dap, Pen, Sarc, Cit, Cav, hLeu, 2-Nal, D-1-Nal, D-2-Nal, Phe(4-OMe),βhTrp, α-MePhe, α-MeTyr, α-MeTrp, β-HPhe, Phe(4-CF₃), 2-2-Indane,1-1-Indane, Cyclobutyl, β-hPhe, Gla, Phe(4-NH₂), hPhe, 1-Nal, Nle,homoamino acids, D-amino acids, 4,4′-Biphenylalanine (Bip),cyclobutyl-Ala, hCha, βhPhe, βGlu, Phe(4-Guanidino),Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], Phe(4-CONH₂),Phe(4-Me), Tyr(Bzl), or Tyr(Me), Phe(3,4-diF₂), Phe(3,4-Cl₂), Phe(3-Me),Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], Phe(Br),Phe(4-CONH₂), Phe(Cl), Phe(4-CN), Phe(4-guadino), Phe(4-Me), Phe(4-NH₂),Phe(4-N₃), Tyr, Tyr(Bzl), or Tyr(Me), Phe(3,4-dimethoxy), 5-HydroxyTrp,Phe(3,4-Cl₂), Tyr(3-tBu), and various N-methylated amino acids andalpha-methyl amino acids. In some embodiments of the present invention,a peptide inhibitor includes one or more non-natural amino acids shownin Table 1A. One having skill in the art will appreciate that othermodified or unnatural amino acids, and various other substitutions ofnatural amino acids with modified or unnatural amino acids, may be madeto achieve similar desired results, and such substitutions are withinthe teaching and spirit of the present invention. In certainembodiments, peptide inhibitors of the present invention include any ofthose described herein, including but not limited to any of thosecomprising an amino acid sequence or peptide inhibitor structure shownin any one of the tables herein, including Tables 3A-3H, 4A, 4B, 5A-5C,6, or 7-18, or the accompanying figures, wherein one or more residues issubstituted with a modified or unnatural amino acid.

The present invention also includes any of the peptide inhibitorsdescribed herein in either a free or a salt form. Thus, embodiments ofany of the peptide inhibitors described herein (and related methods ofuse thereof) include a pharmaceutically acceptable salt of the peptideinhibitor.

The present invention also includes variants of any of the peptideinhibitors described herein, including but not limited to any of thosecomprising a sequence shown in any one of Tables 3A-3H, 4A, 4B, 5A-5C,6, or 7-18, wherein one or more L-amino acid residue is substituted withthe D isomeric form of the amino acid residue, e.g., an L-Ala issubstituted with a D-Ala.

In particular embodiments of the peptide inhibitors described herein,they comprise one or more unnatural or non-natural amino acid residue.

The present invention also includes any of the peptide monomerinhibitors described herein linked to a linker moiety, including any ofthe specific linker moieties described herein. In particularembodiments, a linker is attached to an N-terminal or C-terminal aminoacid, while in other embodiments, a linker is attached to an internalamino acid. In particular embodiments, a linker is attached to twointernal amino acids, e.g., an internal amino acid in each of twomonomer subunits that form a dimer. In some embodiments of the presentinvention, a peptide inhibitor is attached to one or more linkermoieties shown in Tables 2A or 2B.

The present invention also includes peptides comprising a peptidemonomer subunit having at least 90%, at least 95%, at least 98%, or atleast 99% sequence identity to a peptide inhibitor described herein.

In certain embodiments, a peptide inhibitor or a monomer subunit of apeptide inhibitor of the present invention comprises, consistsessentially of, or consists of 7 to 35 amino acid residues, 8 to 35amino acid residues, 9 to 35 amino acid residues, 10 to 35 amino acidresidues, 7 to 25 amino acid residues, 8 to 25 amino acid residues, 9 to25 amino acid residues, 10 to 25 amino acid residues, 7 to 20 amino acidresidues, 8 to 20 amino acid residues, 9 to 20 amino acid residues, 10to 20 amino acid residues, 7 to 18 amino acid residues, 8 to 18 aminoacid residues, 9 to 18 amino acid residues, or 10 to 18 amino acidresidues, and, optionally, one or more additional non-amino acidmoieties, such as a conjugated chemical moiety, e.g., a PEG or linkermoiety. In particular embodiments, a peptide inhibitor of the presentinvention (or a monomer subunit thereof), including but not limited tothose of any embodiment of Formula I, Formula II, Formula III, FormulaIV, Formula V or Formula VI is greater than 10, greater than 12, greaterthan 15, greater than 20, greater than 25, greater than 30 or greaterthan 35 amino acids, e.g., 35 to 50 amino acids. In certain embodiments,a peptide inhibitor (or a monomer subunit thereof) is less than 50, lessthan 35, less than 30, less than 25, less than 20, less than 15, lessthan 12, or less than 10 amino acids. In particular embodiments, amonomer subunit of a peptide inhibitor (or a peptide monomer inhibitor)comprises or consists of 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35amino acid residues. In particular embodiments, a monomer subunit of apeptide inhibitor of the present invention comprises or consists of 10to 18 amino acid residues and, optionally, one or more additionalnon-amino acid moieties, such as a conjugated chemical moiety, e.g., aPEG or linker moiety. In various embodiments, the monomer subunitcomprises or consists of 7 to 35 amino acid residues, 7 to 20 amino acidresidues, 8 to 20 amino acid residues, 9 to 20 amino acid residues, 10to 20 amino acid residues, 8 to 18 amino acid residues, 8 to 19 aminoacid residues, 8 to 18 amino acid residues, 9 to 18 amino acid residues,or 10 to 18 amino acid residues. In particular embodiments of any of thevarious Formulas described herein, X comprises or consists of 7 to 35amino acid residues, 8 to 35 amino acid residues, 9 to 35 amino acidresidues, 10 to 35 amino acid residues, 7 to 25 amino acid residues, 8to 25 amino acid residues, 9 to 25 amino acid residues, 10 to 25 aminoacid residues, 7 to 18 amino acid residues, 8 to 18 amino acid residues,9 to 18 amino acid residues, or 10 to 18 amino acid residues.

Certain illustrative peptide inhibitors described herein comprise 12 ormore amino acid residues. However, the present invention also includespeptide inhibitors comprising a fragment of any of the peptide sequencesdescribed herein, including peptide inhibitors having 7, 8, 9, 10, or 11amino acid residues. For example, peptide inhibitors of the presentinvention include peptides comprising or consisting of X4-X9, X4-X10,X4-X11, X4-X12, X4-X13, X4-X14, X4-X15, or X4-X16. In particularembodiments, the present invention includes peptide inhibitors havingany of the sequences described herein, including but not limited to,those shown in Ix, Ia-It, IIa-IId, IIIa-IIIe, Iva, IVb, V or VI, or anyof the tables provided herein, wherein one or more of X10, X11, X12,X13, X14, X15, or X16 is absent. In particular embodiments, one or moreof X13, X14, X15 or X16 is absent.

In particular embodiments of the present invention, the peptideinhibitors, or X regions thereof, are not present within an antibody. Inparticular embodiments, the peptide inhibitors, or X regions thereof,are not present within a V_(H) or V_(L) region of an antibody.

In particular embodiments of the peptide inhibitors described herein,they comprise one or more unnatural or non-natural amino acid residue.

In particular embodiments, peptide inhibitors of the present inventionare cyclized via a cyclic amide bond, a disulfide bond, or a thioetherbond. In particular embodiments, the bond is an intramolecular bondbetween two amino acid residues within the peptide inhibitor or amonomer subunit thereof.

Peptide Inhibitors

Peptide inhibitors of the present invention include peptides having anyof the amino acid sequences described herein, compounds having any ofthe structures described herein, including compounds comprising any ofthe peptide sequences described herein, and dimers of any of suchpeptides and compounds. Peptide inhibitors on the present inventioninclude both peptides not having and those having a bond between X4 andX9, e.g., before and after a cross-link is introduced between X4 and X9.Illustrative peptides of the invention comprise an amino acid sequenceor structure described in any of the accompanying tables, Examples andfigures.

In certain embodiments, the present invention includes a peptideinhibitor of an interleukin-23 receptor, or a pharmaceuticallyacceptable salt or solvate thereof, wherein the peptide inhibitorcomprises an amino acid sequence of Formula (Xa):

X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (Xa)

whereinX1 is any amino acid or absent;X2 is any amino acid or absent;X3 is any amino acid or absent;X4 is any amino acid or chemical moiety capable of forming a bond withX9;X5 is any amino acid;X6 is any amino acid;X7 is any amino acid;X8 is any amino acid;X9 is any amino acid or chemical moiety capable of forming a bond withX4;X10 is any amino acid;X11 is any amino acid;X12 is any amino acid;X13 is any amino acid;X14 is any amino acid;X15 is any amino acid,X16 is any amino acid or absent;X17 is any amino acid or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent,

wherein X4 and X9 are capable of forming a bond with each other. Inparticular embodiments, the bond is a disulfide bond, a thioether bond,a lactam bond, a triazole ring, a selenoether bond, a diselenide bond,or an olefin bond. In certain embodiments, the peptide inhibitor iscyclized via the bond between X4 and X9. In certain embodiments, thepeptide inhibitor inhibits the binding of an interleukin-23 (IL-23) toan IL-23 receptor. In particular embodiments, when X4 is not an aminoacid, then X1, X2, and X3 are absent.

In one embodiment of the peptide inhibitor of Formula Xa,

X1 is absent;X2 is absent;X3 is Glu, D-Glu, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, (D)Gln orabsent;

X4 is Cys, Abu or Pen; X5 is Ala, α-MeOrn, α-MeSer, Cit, Dap, Dab,Dap(Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn, Gln, Arg, Ser or Thr; X6is Asp or Thr; X7 is Trp or 6-Chloro-Trp; X8 is Glu, Gln or Val; X9 isCys, Abu or Pen;

X10 is 2-Nal, a Phe analog, Tyr, or a Tyr analog, wherein in particularembodiments, X10 is 2-Nal, Phe(3,4-diF₂), Phe(3,4-Cl₂), Phe(3-Me),Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], Phe(Br),Phe(4-CONH₂), Phe(C1), Phe(4-CN), Phe(4-guadino), Phe(4-Me), Phe(4-NH₂),Phe(4-N3), Tyr, Tyr(Bzl), or Tyr(Me);X11 is 1-Nal, 2-Nal, Phe(3,4-dimethoxy), 5-HydroxyTrp, Phe(3,4-Cl₂), Trpor Tyr(3-tBu);X12 is 3-Pal, Acpc, Acbc, Acvc, Achc, Agp, Aib, α-DiethylGly, α-MeLys,α-MeLys(Ac), α-MeLeu, α-α-MeOrn, α-MeSer, α-MeVal, Cav, Cha, Cit, Cpa,D-Asn, Glu, His, hLeu, hArg, Lys, Leu, Octgly, Orn, piperidine, Arg,Ser, Thr or THP;X13 is Cit, Asp, Dab, Dap, Phe, His, Dap(Peg2-Ac), Dap(pyroglutaricacid), Glu, hArg, Lys, Lys(Ac), Lys(Benzoic acid), Lys(glutaric acid),Lys(IVA), Lys(Peg4-isoGlu-Palm), Lys(pyroglutaric acid), Lys-succinicacid, Asn, Orn, Gln, Arg, Thr or Val;X14 is Asp, Dab(Ac), Dap(Ac), Phe, His, Lys(Ac), Met, Asn(isobutyl),Gln, Arg, Tyr or Asp(1,4-diaminobutane);X15 is Ala, betaAla, Glu, Gly, Asn, Gln, Arg or Ser,X16 is any amino acid or absent;X17 is any amino acid or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent.

IN certain embodiments, X3 is absent. In particular embodiments, X16,X17, X18, X19 and X20 are absent. In particular embodiments, X4 and X9are Cys, and X4 and X9 are linked via a disulfide bond. In particularembodiments, X4 is Abu and X9 is Pen, and X4 and X9 are linked via athioether bond. In particular embodiments, X4 is Abu and X9 is Cys, andX4 and X9 are linked via a thioether bond.

In another embodiment of the peptide inhibitor of Formula Xa,

X1 is absent;X2 is absent;X3 is Glu, D-Glu, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, (D)Gln orabsent;

X4 is Cys, Abu or Pen; X5 is Ala, α-MeOrn, α-MeSer, Cit, Dap, Dab,Dap(Ac), Gly, Lys, Asn, Orn, Gln, Arg, Ser or Thr; X6 is Asp or Thr; X7is Trp or 6-Chloro-Trp; X8 is Gln or Val; X9 is Cys, Abu or Pen;

X10 is 2-Nal, a Phe analog, Tyr, or a Tyr analog, wherein in particularembodiments, X10 is 2-Nal, Phe(3,4-diF₂), Phe(3-Me),Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], Phe(Br),Phe(4-CONH₂), Phe(4-Cl), Phe(4-CN), Phe(4-guadino), Phe(4-Me),Phe(4-NH₂), Phe(4-N₃), Tyr, Tyr(Bzl), or Tyr(Me);X11 is 1-Nal, 2-Nal, Phe(3,4-dimethoxy), 5-HydroxyTrp, Phe(3,4-Cl₂), Trpor Tyr(3-tBu);X12 is 3-Pal, Acpc, Acbc, Acvc, Achc, Agp, Aib, α-DiethylGly, α-MeLys,α-MeLys(Ac), α-MeLeu, α-MeOrn, α-MeSer, α-MeVal, Cav, Cha, Cit, Cpa,D-Asn, His, hLeu, hArg, Lys, Leu, Octgly, Orn,4-amino-4-carboxy-piperidine, or THP;X13 is Cit, Asp, Dab, Dap, Phe, His, Dap(Peg2-Ac), Dap(pyroglutaricacid), Glu, hArg, Lys, Lys(Ac), Lys(Benzoic acid), Lys(glutaric acid),Lys(IVA), Lys(Peg4-isoGlu-Palm), Lys(pyroglutaric acid), Lys-succinicacid, Asn, Orn, Gln, Arg, Thr or Val;

X14 is Dab(Ac), Dap(Ac), Phe, His, Lys(Ac), Met, Asn, Gln, Arg, or Tyr;X15 is Ala, βAla, Gly, Asn, Gln, or Ser,

X16 is any amino acid or absent;X17 is any amino acid or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent.

In some embodiments, X3 is absent. In particular embodiments, X16, X17,X18, X19 and X20 are absent. In particular embodiments, X4 and X9 areCys, and X4 and X9 are linked via a disulfide bond. In particularembodiments, X4 is Abu and X9 is Pen, and X4 and X9 are linked via athioether bond. In particular embodiments, X4 is Abu and X9 is Cys, andX4 and X9 are linked via a thioether bond.

In another embodiment of the peptide inhibitor of Formula Xa,

X1 is absent;X2 is absent;X3 is Glu, D-Glu, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, (D)Gln orabsent;

X4 is Cys, Abu or Pen; X5 is Dap, Dap(Ac), Gly, Lys, Gln, Arg, Ser, Thror Asn; X6 is Thr; X7 is Trp or 6-Chloro-Trp; X8 is Gln; X9 is Cys, Abuor Pen;

X10 is 2-Nal, a Phe analog, Tyr, or a Tyr analog, wherein in particularembodiments, X10 is 2-Nal, Phe(3-Me), Phe[4-(2-aminoethoxy)],Phe[4-(2-acetylaminoethoxy)], Phe(4-CONH₂), Phe(4-Me), Phe(4-NH₂), Tyr,Tyr(Bzl), or Tyr(Me);X11 is 1-Nal, 2-Nal, Phe(3,4-dimethoxy), Phe(3,4-Cl₂), or Trp;X12 is Acpc, Acbc, Acvc, Achc, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac),α-MeLeu, α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, hLeu, Lys, Leu, Arg orTHP;X13 is Cit, Asp, Dap, Dap(Peg2-Ac), Dap(pyroglutaric acid), Glu, hArg,Lys, Lys(Ac), Lys(Benzoic acid), Lys(glutaric acid), Lys(IVA),Lys(Peg4-isoGlu-Palm), Lys(pyroglutaric acid), Lys(succinic acid), Asn,Orn, Gln, Arg, or Val;

X14 is Dab(Ac), Dap(Ac), His, Lys(Ac), Asn, Gln, or Tyr;

X15 is Ala, betaAla, Gly, Asn, Gln, or Ser,X16 is any amino acid or absent;X17 is any amino acid or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent.

In some embodiments, X3 is absent. In particular embodiments, X16, X17,X18, X19 and X20 are absent. In particular embodiments, X4 and X9 areCys, and X4 and X9 are linked via a disulfide bond. In particularembodiments, X4 is Abu and X9 is Pen, and X4 and X9 are linked via athioether bond. In particular embodiments, X4 is Abu and X9 is Cys, andX4 and X9 are linked via a thioether bond.

In another embodiment of the peptide inhibitor of Formula Xa,

X1 is absent;X2 is absent;X3 is Glu, D-Glu, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, (D)Gln orabsent;

X4 is Cys, Abu or Pen; X5 is Dap, Dap(Ac), Gln, Ser, Thr or Asn; X6 isThr; X7 is Trp; X8 is Gln; X9 is Cys, Abu or Pen;

X10 is a Phe analog, Tyr, or a Tyr analog, wherein in particularembodiments, X10 is Phe[4-(2-aminoethoxy)],Phe[4-(2-acetylaminoethoxy)], Phe(4-CONH₂), Phe(4-Me), Tyr, Tyr(Bzl), orTyr(Me);

X11 is 2-Nal or Trp;

X12 is Acpc, Acbc, Acvc, Achc, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac),α-MeLeu, α-MeOrn, α-MeSer, α-MeVal, hLeu, Leu, or THP;

X13 is Cit, Asp, Glu, Lys, Lys(Ac), Asn, or Gln; X14 is Dab(Ac), Asn, orHis;

X15 is Ala, betaAla, Gly, Asn, or Gln;X16 is any amino acid or absent;X17 is any amino acid or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent.

In some embodiments, X3 is absent. In particular embodiments, X16, X17,X18, X19 and X20 are absent. In particular embodiments, X4 and X9 areCys, and X4 and X9 are linked via a disulfide bond. In particularembodiments, X4 is Abu and X9 is Pen, and X4 and X9 are linked via athioether bond. In particular embodiments, X4 is Abu and X9 is Cys, andX4 and X9 are linked via a thioether bond.

In particular embodiments, the peptide inhibitor comprises the aminoacid sequence set forth in any of the various formula described herein,e.g., Ia-It, IIIa-IIIe, or IV.

In certain embodiments, the present invention includes a peptideinhibitor of an interleukin-23 receptor, wherein the peptide inhibitorhas the structure of Formula I:

R¹—X—R²  (I)

or a pharmaceutically acceptable salt or solvate thereof,

wherein R¹ is a bond, hydrogen, an C1-C6 alkyl, a C6-C12 aryl, a C6-C12aryl C1-C6 alkyl, a C1-C20 alkanoyl, and including PEGylated versionsalone or as spacers of any of the foregoing;

R² is a bond, OH or NH₂; and

X is an amino acid sequence, e.g., an amino acid comprising 7 to 35amino acid residues. In certain embodiments, R² is OH or NH₂.

In certain embodiments, X comprises a sequence of Formula Xa.

In particular embodiments of formula (I), X comprises the sequence ofFormula Ia:

X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (Ia)

whereinX1 is any amino acid or absent;X2 is any amino acid or absent;X3 is any amino acid or absent;X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, Asp, Lys, Orn,Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Sec, 2-chloromethylbenzoicacid, mercapto-propanoic acid, mercapto-butyric acid, 2-chloro-aceticacid, 3-choro-propanoic acid, 4-chloro-butyric acid, 3-chloro-isobutyricacid, Abu, β-azido-Ala-OH, propargylglycine, 2-(3′-butenyl)glycine,2-allylglycine, 2-(3′-butenyl)glycine, 2-(4′-pentenyl)glycine,2-(5′-hexenyl)glycine or absent;

X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu,D-Phe, D-Leu, D-Thr, D-Ser, α-MeOrn, α-MeSer, CitDap, Dab, Dap (Ac),Gly, Lys, Asn, N-Me-Gln, N-Me-Arg, Orn or Gln, X6 is Asp, Thr, Asn, Phe,D-Asp, D-Thr, D-Asn, or D-Phe; X8 is Val, Gln, Glu, or Lys;

X9 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab,D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Asp, Leu, Val, Phe, Ser, Sec, Abu,β-azido-Ala-OH, propargylglycine, 2-2-allylglycine,2-(3′-butenyl)glycine, 2-(4′-pentenyl)glycine, or 2-(5′-hexenyl)glycine;X10 is Tyr, Phe, Phe(3,4-F₂), Phe(3,4-Cl₂), F(3-Me),Phe[4-(2-aminoethoxy)], Phe[4-(2-(acetyl-aminoethoxy)], Phe(4-Br),Phe(4-CONH₂), Phe(4-Cl), Phe(4-CN), Phe(4-guanidino), Phe(4-Me),Phe(4-NH₂), Phe(4-N₃), Phe(4-OMe), Phe(4-OBzl) or Tyr;X11 is Trp, 1-Nal, 2-Nal, Phe(3,4-OMe₂) 5-Hydroxy-Trp, Phe(3,4-Cl₂) orTyr(3-t-Bu)X12 is His, Phe, Arg, N-Me-His, or Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal,t-butyl-Ala, t-butyl-Gly 4-amino-4-carboxy-tetrahydropyran, Achc Acpc,Acbc, Acvc, Agp, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac), α-Me-Leu,α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D)Asn, Glu, hArg, or Lys;X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, βhAla, Aib, Lys(Ac),Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln;X14 is Phe, Tyr βhPhe, Asn, Arg, Gln, Lys(Ac), His; Dap(Ac), Dab(Ac), orAsp;

X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn;

X16 is any amino acid or absent;X17 is any amino acid or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent.

In particular embodiments of Ia: X5 is Ala, Arg, Glu, Phe, Leu, Thr,Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aibor D-Sarc; X10 is Tyr or Phe; X11 is Trp, 1-Nal or 2-Nal; X12 is His,Phe, Arg, N-Me-His, or Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Alaor t-butyl-Gly; X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, βhAla,or Aib; X14 is Phe, Tyr or βhPhe; X15 is Gly, Ser, Thr, Gln, Ala orSarc; X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba, or absent; and X17 isLeu, Lys, Arg, or absent.

In particular embodiments, X4 is present.

In certain embodiments, the peptide inhibitor is cyclized.

In certain embodiments, the peptide inhibitor is linear or not cyclized.

In certain embodiments, the peptide inhibitor is cyclized, or containsan intramolecular bond, between X4 and X9.

In certain embodiments of Formula I, X comprises the sequence of FormulaIb:

X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (Ib),

wherein:

X1 is any amino acid or absent;X2 is any amino acid or absent;X3 is any amino acid or absent;X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Asp, Lys, Orn, Dap,Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Sec, 2-chloromethylbenzoic acid,mercapto-propanoic acid, mercapto-butyric acid, 2-chloro-acetic acid,3-choro-propanoic acid, 4-chloro-butyric acid, 3-chloro-isobutyric acid,Abu, β-azido-Ala-OH, propargylglycine, 2-(3′-butenyl)glycine,2-2-allylglycine, 2-(3′-butenyl)glycine, 2-(4′-pentenyl)glycine,2-(5′-hexenyl)glycine, or absent;

X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu,D-Phe, D-Leu, D-Thr, D-Ser, α-MeOrn, α-MeSer, CitDap, Dab, Dap (Ac),Gly, Lys, Asn, N-Me-Gln, N-Me-Arg, Orn or Gln; X6 is Asp, Thr, Asn, Phe,D-Asp, D-Thr, D-Asn, or D-Phe; X8 is Val, Gln, Glu, or Lys;

X9 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab,D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Asp, Sec, Abu, β-azido-Ala-OH,propargylglycine, 2-allylglycine, 2-(3′-butenyl)glycine,2-(4′-pentenyl)glycine, or 2-(5′-hexenyl)glycine;X10 is Tyr, Phe, Phe(3,4-F₂), Phe(3,4-Cl₂), F(3-Me),Phe[4-(2-aminoethoxy)], Phe[4-(2-(acetyl-aminoethoxy)], Phe(4-Br),Phe(4-CONH₂), Phe(4-C1), Phe(4-CN), Phe(4-guanidino), Phe(4-Me),Phe(4-NH₂), Phe(4-N₃), Phe(4-OMe), Phe(4-OBzl) or TyrX11 is Trp, 1-Nal, 2-Nal, Phe(3,4-OMe₂) 5-Hydroxy-Trp, Phe(3,4-Cl₂),Tyr(3-t-Bu)X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal,t-butyl-Ala, t-butyl-Gly4-amino-4-carboxy-tetrahydropyran, Achc Acpc,Acbc, Acvc, Agp, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac), α-Me-Leu,α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D)Asn, Glu, hArg, or LysX13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, βhAlaAib, Lys(Ac), Cit,Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or GlnX14 is Phe, Tyr, or βhPhe, Asn, Arg, Gln, Lys(Ac), His; Dap(Ac), Dab(Ac)or Asp;

X15 is Gly, Ser, Thr, Gln, Ala, or Sarc, β-Ala, Glu, Arg or Asn;

X16 is any amino acid or absent;X17 is any amino acid, or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent.

In particular embodiments of Ib: X5 is Ala, Arg, Glu, Phe, Leu, Thr,Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aibor D-Sarc; X10 is Tyr or Phe; X11 is Trp, 1-Nal or 2-Nal; X12 is His,Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala ort-butyl-Gly; X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, βhAla orAib; X14 is Phe, Tyr or βhPhe; X15 is Gly, Ser, Thr, Gln, Ala, or Sarc;X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba, or absent; and X17 is Leu,Lys, Arg, or absent.

In particular embodiments, X4 is present.

In certain embodiments, the peptide inhibitor is cyclized.

In certain embodiments, the peptide inhibitor is linear or not cyclized.

In certain embodiments, the peptide inhibitor is cyclized, or containsan intramolecular bond, between X4 and X9.

In certain embodiments of Formula I, X comprises the sequence of FormulaIc:

X1-X2-X3-X4-X5-X6-W-X8-X9-Y-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (Ic)

wherein

X1 is any amino acid or absent;X2 is any amino acid or absent;X3 is any amino acid or absent;X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, Asp, Lys, Orn,Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Sec, 2-chloromethylbenzoicacid, mercapto-propanoic acid, mercapto-butyric acid, 2-chloro-aceticacid, 3-choro-propanoic acid, 4-chloro-butyric acid, 3-chloro-isobutyricacid, Abu, β-azido-Ala-OH, propargylglycine, 2-allylglycine,2-(3′-butenyl)glycine, 2-(4′-pentenyl)glycine, 2-(5′-hexenyl)glycine, orabsent;

X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu,D-Phe, D-Leu, D-Thr, D-Ser, α-MeOrn, α-MeSer, CitDap, Dab, Dap (Ac),Gly, Lys, Asn, N-Me-Gln, N-Me-Arg, Orn or Gln X6 is Asp, Thr, Asn, Phe,D-Asp, D-Thr, D-Asn, or D-Phe; X8 is Val, Gln, Glu, or Lys;

X9 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab,D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Asp, Sec, Abu, β-azido-Ala-OH,propargylglycine, 2-allylglycine, 2-(3′-butenyl)glycine,2-(4′-pentenyl)glycine, or 2-(5′-hexenyl)glycine;X11 is Trp, 1-Nal, 2-Nal Phe(3,4-OMe₂) 5-Hydroxy-Trp, Phe(3,4-Cl₂) orTyr(3-t-Bu)X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal,t-butyl-Ala t-butyl-Gly; 4-amino-4-carboxy-tetrahydropyran, Achc Acpc,Acbc, Acvc, Agp, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac), α-Me-Leu,α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D)Asn, Glu, hArg, or LysX13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, βhAla, or Aib, Lys(Ac),Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or GlnX14 is Phe, Tyr, βhPhe, Asn, Arg, Gln, Lys(Ac), His; Dap(Ac), Dab(Ac) orAsp;

X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn;

X16 is any amino acid or absent;X17 is any amino acid or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent.

In particular embodiments of Ic, X5 is Ala, Arg, Glu, Phe, Leu, Thr,Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib,or D-Sarc; X11 is Trp, 1-Nal, or 2-Nal; X12 is His, Phe, Arg, N-Me-His,Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala or t-butyl-Gly; X13 isThr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, βhAla, or Aib; X14 is Phe, Tyr,or βhPhe; X15 is Gly, Ser, Thr, Gln, Ala, or Sarc; X16 is Asp, Glu, Ala,AEA, AEP, βhAla, Gaba, or absent; and X17 is Leu, Lys, Arg, or absent.

In particular embodiments, X4 is present.

In certain embodiments, the peptide inhibitor is cyclized.

In certain embodiments, the peptide inhibitor is linear or not cyclized.

In certain embodiments, the peptide inhibitor is cyclized, or containsan intramolecular bond, between X4 and X9.

In certain embodiments of Formula I, X comprises the sequence of FormulaId:

X1-X2-X3-C-X5-X6-W-X8-C-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (Id)

wherein

X1 is any amino acid or absent;X2 is any amino acid or absent;X3 is any amino acid or absent;

X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu,D-Phe, D-Leu, D-Thr, D-Ser, α-MeOrn, α-MeSer, CitDap, Dab, Dap (Ac),Gly, Lys, Asn, N-Me-Gln, N-Me-Arg, Orn or Gln; X6 is Asp, Thr, Asn, Phe,D-Asp, D-Thr, D-Asn, or D-Phe; X8 is Val, Gln, Glu, or Lys;

X10 is Tyr Phe, Phe(3,4-F₂), Phe(3,4-Cl₂), F(3-Me),Phe[4-(2-aminoethoxy)], Phe[4-(2-(acetyl-aminoethoxy)], Phe(4-Br),Phe(4-CONH₂), Phe(4-Cl), Phe(4-CN), Phe(4-guanidino), Phe(4-Me),Phe(4-NH₂), Phe(4-N₃), Phe(4-OMe), Phe(4-OBzl) or TyrX11 is Trp, 1-Nal, 2-Nal, Phe(3,4-OMe₂) 5-Hydroxy-Trp, Phe(3,4-Cl₂),Tyr(3-t-Bu)X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal,t-butyl-Ala, t-butyl-Gly, 4-amino-4-carboxy-tetrahydropyran, Achc Acpc,Acbc, Acvc, Agp, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac), α-Me-Leu,α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D)Asn, Glu, hArg, or LysX13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, βhAla, Aib, Lys(Ac),Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or GlnX14 is Phe, Tyr, βhPhe, Asn, Arg, Gln, Lys(Ac), His, Dap(Ac), Dab(Ac) orAsp;

X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn;

X16 is any amino acid or absent;X17 is any amino acid or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent,

wherein X4 and X9 are optionally linked by a intramolecular disulphidebridge.

In certain embodiments of Id: X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser,Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib, orD-Sarc; X10 is Tyr or Phe; X11 is Trp, 1-Nal, or 2-Nal; X12 is His, Phe,Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, ort-butyl-Gly; X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, βhAla, orAib; X14 is Phe, Tyr, or βhPhe; X15 is Gly, Ser, Thr, Gln, Ala, or Sarc;X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba, or absent; and X17 is Leu,Lys, Arg, or absent.

In certain embodiments of Formula I, X comprises the sequence of FormulaIe:

X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (Ie)

wherein

X1 is any amino acid or absent;X2 is any amino acid or absent;X3 is any amino acid or absent;X4 is Pen, hCys, D-Pen, D-Cys, or D-hCys;

X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu,D-Phe, D-Leu, D-Thr, D-Ser, α-MeOrn, α-MeSer, CitDap, Dab, Dap (Ac),Gly, Lys, Asn, N-Me-Gln, N-Me-Arg, Orn or Gln; X6 is Asp, Thr, Asn, Phe,D-Asp, D-Thr, D-Asn, or D-Phe; X8 is Val, Gln, Glu, or Lys;

X9 is Pen, hCys, D-Pen, D-Cys, D-hCys;X10 is Tyr, Phe Phe(3,4-F₂), Phe(3,4-Cl₂), F(3-Me),Phe[4-(2-aminoethoxy)], Phe[4-(2-(acetyl-aminoethoxy)], Phe(4-Br),Phe(4-CONH₂), Phe(4-C1), Phe(4-CN), Phe(4-guanidino), Phe(4-Me),Phe(4-NH₂), Phe(4-N₃), Phe(4-OMe), Phe(4-OBzl) or Tyr;X11 is Trp, 1-Nal, 2-Nal, Phe(3,4-OMe₂) 5-Hydroxy-Trp, Phe(3,4-Cl₂) orTyr(3-t-Bu);X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal,t-butyl-Ala, t-butyl-Gly, 4-amino-4-carboxy-tetrahydropyran, Achc Acpc,Acbc, Acvc, Agp, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac), α-Me-Leu,α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D)Asn, Glu, hArg, or Lys;X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, βhAla, Aib, Lys(Ac),Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln;X14 is Phe, Tyr, βhPhe, Asn, Arg, Gln, Lys(Ac), His; Dap(Ac), Dab(Ac) orAsp;

X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn;

X16 is any amino acid or absent;X17 is any amino acid or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent,

wherein X4 and X9 are optionally linked by a intramolecular disulphidebridge.

In certain embodiments of Ie: X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser,Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib, orD-Sarc; X10 is Tyr or Phe; X11 is Trp, 1-Nal, or 2-Nal; X12 is His, Phe,Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, ort-butyl-Gly; X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, βhAla, orAib; X14 is Phe, Tyr, or βhPhe; X15 is Gly, Ser, Thr, Gln, Ala, or Sarc;X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba, or absent; and X17 is Leu,Lys, Arg, or absent.

In particular embodiments, X4 is present.

In certain embodiments, the peptide inhibitor is cyclized.

In certain embodiments, the peptide inhibitor is linear or not cyclized.

In certain embodiments, the peptide inhibitor is cyclized, or containsan intramolecular bond, between X4 and X9.

In particular embodiments, X4 and X9 and both Pen.

In certain embodiments of Formula I, X comprises the sequence of FormulaIf:

X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (If)

wherein

X1 is any amino acid or absent;X2 is any amino acid or absent;X3 is any amino acid or absent;

X4 is Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, orAsp; X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg,D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap(Ac), Gly, Lys, Asn, N-Me-Gln, N-Me-Arg, Orn or Gln; X6 is Asp, Thr,Asn, Phe, D-Asp, D-Thr, D-Asn, or D-Phe; X8 is Val, Gln, Glu, or Lys; X9is Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, or Asp;

X10 is Tyr, Phe, Phe(3,4-F₂), Phe(3,4-Cl₂), F(3-Me),Phe[4-(2-aminoethoxy)], Phe[4-(2-(acetyl-aminoethoxy)], Phe(4-Br),Phe(4-CONH₂), Phe(4-C1), Phe(4-CN), Phe(4-guanidino), Phe(4-Me),Phe(4-NH₂), Phe(4-N₃), Phe(4-OMe), Phe(4-OBzl) or Tyr;X11 is Trp, 1-Nal, 2-Nal, Phe(3,4-OMe₂) 5-Hydroxy-Trp, Phe(3,4-Cl₂) orTyr(3-t-Bu);X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal,t-butyl-Ala, or t-butyl-Gly, 4-amino-4-carboxy-tetrahydropyran, AchcAcpc, Acbc, Acvc, Agp, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac),α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D)Asn, Glu, hArg,or Lys;X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, βhAla, Aib, Lys(Ac),Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln;X14 is Phe, Tyr, βhPhe, Asn, Arg, Gln, Lys(Ac), His; Dap(Ac), Dab(Ac) orAsp;

X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn;

X16 is any amino acid or absent;X17 is any amino acid or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent,

wherein X4 and X9 are optionally cyclized through an intramolecularbond.

In certain embodiments of If: X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser,Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib, orD-Sarc; X6 is Asp, Thr, Asn, Phe, D-Asp, D-Thr, D-Asn, or D-Phe; X8 isVal, Gln, Glu, or Lys; X9 is Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab,D-Asp, D-Glu, D-Lys, or Asp; X10 is Tyr or Phe; X11 is Trp, 1-Nal, or2-Nal; X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu,3-Pal, t-butyl-Ala, or t-butyl-Gly; X13 is Thr, Sarc, Glu, Phe, Arg,Leu, Lys, Val, βhAla, or Aib; X14 is Phe, Tyr, or βhPhe; X15 is Gly,Ser, Thr, Gln, Ala, or Sarc; X16 is Asp, Glu, Ala, AEA, AEP, βhAla,Gaba, or absent; and X17 is Leu, Lys, Arg, or absent.

In certain embodiments, the intramolecular bond is a lactam bond.

In certain embodiments of Formula I, X comprises the sequence of FormulaIg:

X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (Ig)

wherein

X1 is any amino acid or absent;X2 is any amino acid or absent;X3 is any amino acid or absent;X4 is β-azido-Ala-OH, or propargylglycine;

X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu,D-Phe, D-Leu, D-Thr, D-Ser, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap(Ac),Gly, Lys, Asn, N-MeGln, N-MeArg, Orn or Gln; X6 is Asp, Thr, Asn, Phe,D-Asp, D-Thr, D-Asn, or D-Phe; X8 is Val, Gln, Glu, or Lys;

X9 is β-azido-Ala-OH or propargylglycine;X10 is Tyr, Phe, Phe(3,4-F₂), Phe(3,4-Cl₂), F(3-Me),Phe[4-(2-aminoethoxy)], Phe[4-(2-(acetyl-aminoethoxy)], Phe(4-Br),Phe(4-CONH₂), Phe(4-C1), Phe(4-CN), Phe(4-guanidino), Phe(4-Me),Phe(4-NH₂), Phe(4-N₃), Phe(4-OMe), Phe(4-OBzl) or Tyr;X11 is Trp, 1-Nal, 2-Nal, Phe(3,4-OMe₂) 5-Hydroxy-Trp, Phe(3,4-Cl₂) orTyr(3-t-Bu)X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal,t-butyl-Ala, or t-butyl-Gly, 4-amino-4-carboxy-tetrahydropyran, AchcAcpc, Acbc, Acvc, Agp, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac),α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D)Asn, Glu, hArg,or Lys;X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, βhAla, Aib, Lys(Ac),Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln;X14 is Phe, Tyr, βhPhe, Asn, Arg, Gln, Lys(Ac), His; Dap(Ac), Dab(Ac) orAsp;

X15 is Gly, Ser, Thr, Gln, Ala, or Sarc, β-Ala, Glu, Arg or Asn;

X16 is any amino acid or absent;X17 is any amino acid or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent,

wherein X4 and X9 are optionally cyclized through an intramoleculartriazole ring.

In particular embodiments of Ig: X5 is Ala, Arg, Glu, Phe, Leu, Thr,Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib,or D-Sarc; X6 is Asp, Thr, Asn, Phe, D-Asp, D-Thr, D-Asn, or D-Phe; X8is Val, Gln, Glu, or Lys; X9 is β-azido-Ala-OH or propargylglycine; X10is Tyr or Phe; X11 is Trp, 1-Nal, or 2-Nal; X12 is His, Phe, Arg,N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, ort-butyl-Gly; X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, βhAla, orAib; X14 is Phe, Tyr, or βhPhe; X15 is Gly, Ser, Thr, Gln, Ala, or Sarc;X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba, or absent; and X17 is Leu,Lys, Arg, or absent.

In certain embodiments of Formula I, X comprises the sequence of FormulaIh:

(SEQ ID NO: 1111) X1-X2-X3-X4-X5-X6-W-X8-X9-Y-X11-H-X13-F-X15-X16-X17-X18-X19-X20 (Ih)

wherein

X1 is any amino acid or absent;X2 is any amino acid or absent;X3 is any amino acid or absent;X4 is 2-allylglycine, 2-(3′-butenyl)glycine, 2-(4′-pentenyl)glycine, or2-(5′-hexenyl)glycine;

X5 is Ala, Arg, Sarc, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap(Ac), Gly,Lys, Asn, N-MeGln, N-MeArg, Orn or Gln; X6 is Asp, Thr, or Asn; X8 isVal, Gln, or Glu;

X9 is 2-allylglycine, 2-(3′-butenyl)glycine, 2-(4′-pentenyl)glycine, or2-(5′-hexenyl)glycine;X11 is Trp, 1-Nal, 2-Nal, Phe(3,4-OMe₂) 5-Hydroxy-Trp, Phe(3,4-Cl₂) orTyr(3-t-Bu)X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, βhAla, Val, Aib, Lys(Ac),Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln;

X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn;

X16 is any amino acid or absent;X17 is any amino acid or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent,

wherein X4 and X9 are optionally cyclized via an intramolecular ringclosing methasis to give the corresponding olefins.

In particular embodiments of Ih: X5 is Ala, Arg, or Sarc; X6 is Asp,Thr, or Asn; X11 is Trp, 1-Nal, or 2-Nal; X13 is Thr, Sarc, Glu, Phe,Arg, Leu, Lys, βhAla, Val, or Aib; X15 is Gly, Ser, Thr, Gln, Ala, orSarc; X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba, or absent; and X17 isLeu, Lys, Arg, or absent.

In certain embodiments of Formula I, X comprises the sequence of FormulaIi:

X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (Ii),

wherein:

X1 is any amino acid or absent;X2 is any amino acid or absent;X3 is any amino acid or absent;X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, 2-chloromethylbenzoic acid,mercapto-propanoic acid, mercapto-butyric acid, 2-chloro-acetic acid,3-choro-propanoic acid, 4-chloro-butyric acid, or 3-chloro-isobutyricacid;

X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu,D-Phe, D-Leu, D-Thr, D-Ser, D-Aib, or D-Sarc, α-MeOrn, α-MeSer, Cit,Dap, Dab, Dap(Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn or Gln; X6 isAsp, Thr, Asn, Phe, D-Asp, D-Thr, D-Asn, or D-Phe; X8 is Val, Gln, Glu,or Lys;

X9 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, or Abu;X10 is Tyr, Phe, Phe(3,4-F₂), Phe(3,4-Cl₂), F(3-Me),Phe[4-(2-aminoethoxy)], Phe[4-(2-(acetyl-aminoethoxy)], Phe(4-Br),Phe(4-CONH₂), Phe(4-C1), Phe(4-CN), Phe(4-guanidino), Phe(4-Me),Phe(4-NH₂), Phe(4-N₃), Phe(4-OMe), Phe(4-OBzl) or Tyr;X11 is Trp, 1-Nal, 2-Nal, Phe(3,4-OMe₂) 5-Hydroxy-Trp, Phe(3,4-Cl₂) orTyr(3-t-Bu)X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal,t-butyl-Ala, t-butyl-Gly, 4-amino-4-carboxy-tetrahydropyran, Achc Acpc,Acbc, Acvc, Agp, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac), α-Me-Leu,α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D)Asn, Glu, hArg, or Lys;X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, βhAla, Aib, Lys(Ac),Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln;X14 is Phe, Tyr, βhPhe, Asn, Arg, Gln, Lys(Ac), His; Dap(Ac), Dab(Ac) orAsp;

X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn;

X16 is any amino acid or absent;X17 is any amino acid or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent,

wherein X4 and X9 are optionally cyclized via an intramolecularthioether bond.

In particular embodiments of Ii: X5 is Ala, Arg, Glu, Phe, Leu, Thr,Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib,or D-Sarc; X6 is Asp, Thr, Asn, Phe, D-Asp, D-Thr, D-Asn, or D-Phe; X10is Tyr or Phe; X11 is Trp, 1-Nal, or 2-Nal; X12 is His, Phe, Arg,N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, ort-butyl-Gly; X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, βhAla, orAib; X14 is Phe, Tyr, or βhPhe; X15 is Gly, Ser, Thr, Gln, Ala, or Sarc;X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba, or absent; and X17 is Leu,Lys, Arg, or absent.

In certain embodiments of Formula I, X comprises the sequence of FormulaIj:

X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (Ij),

wherein:

X1 is any amino acid or absent;X2 is any amino acid or absent;X3 is any amino acid or absent;X4 is Sec, 2-chloromethylbenzoic acid, 3-choro-propanoic acid,4-chloro-butyric acid, 3-chloro-isobutyric acid, or Abu;

X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu,D-Phe, D-Leu, D-Thr, D-Ser, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap(Ac),Gly, Lys, Asn, N-MeGln, N-MeArg, Orn or Gln; X6 is Asp, Thr, Asn, Phe,D-Asp, D-Thr, D-Asn, or D-Phe; X8 is Val, Gln, Glu, or Lys; X9 is Sec orAbu;

X10 is Tyr, Phe, Phe(3,4-F₂), Phe(3,4-Cl₂), F(3-Me),Phe[4-(2-aminoethoxy)], Phe[4-(2-aminoethoxy),Phe[4-(2-(acetyl-aminoethoxy)], Phe(4-Br), Phe(4-CONH₂), Phe(4-C1),Phe(4-CN), Phe(4-guanidino), Phe(4-Me), Phe(4-NH₂), Phe(4-N₃),Phe(4-OMe), Phe(4-OBzl) or Tyr;X11 is Trp, 1-Nal, 2-Nal, Phe(3,4-OMe₂) 5-Hydroxy-Trp, Phe(3,4-Cl₂) orTyr(3-t-Bu);X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal,t-butyl-Ala, t-butyl-Gly, 4-amino-4-carboxy-tetrahydropyran, Achc, Acpc,Acbc, Agp, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac), α-Me-Leu, α-MeOrn,α-MeSer, α-MeVal, Cha, Cit, Cpa, (D)Asn, Glu, hArg, or Lys;X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, βhAla, Aib, Lys(Ac),Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln;X14 is Phe, Tyr, βhPhe, Asn, Arg, Gln, Lys(Ac), His; Dap(Ac), Dab(Ac) orAsp;

X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn;

X16 is any amino acid or absent;X17 is any amino acid or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent,

wherein X4 and X9 are optionally cyclized via an intramolecularthioseleno or diselenide bond.

In particular embodiments of Ij: X5 is Ala, Arg, Glu, Phe, Leu, Thr,Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib,or D-Sarc; X10 is Tyr or Phe; X11 is Trp, 1-Nal, or 2-Nal; X12 is His,Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala,or t-butyl-Gly; X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, βhAla,or Aib; X14 is Phe, Tyr, or βhPhe; X15 is Gly, Ser, Thr, Gln, Ala, orSarc; X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba, or absent; and X17 isLeu, Lys, Arg, or absent.

In certain embodiments of Formula I, X comprises the sequence of FormulaIk:

X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (Ik),

wherein

X1 is any amino acid or absent;X2 is any amino acid or absent;X3 is any amino acid or absent;X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, Asp, Lys, Orn,Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys or absent;

X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu,D-Phe, D-Leu, D-Thr, D-Ser, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap(Ac),Gly, Lys, Asn, N-MeGln, N-MeArg, Orn or Gln; X6 is Asp, Thr, Asn, Phe,D-Asp, D-Thr, D-Asn, or D-Phe; X8 is Val, Gln, Glu, or Lys;

X9 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab,D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Asp, Leu, Val, Phe, or Ser;X10 is Tyr, Phe, Phe(3,4-F₂), Phe(3,4-Cl₂), F(3-Me),Phe[4-(2-aminoethoxy)], Phe[4-(2-(acetyl-aminoethoxy)], Phe(4-Br),Phe(4-CONH₂), Phe(4-Cl), Phe(4-CN), Phe(4-guanidino), Phe(4-Me),Phe(4-NH₂), Phe(4-N₃), Phe(4-OMe), Phe(4-OBzl) or Tyr;

X11 is Trp, 1-Nal, 2-Nal, Phe(3,4-OMe₂) 5-Hydroxy-Trp, Phe(3,4-C2) orTyr(3-t-Bu);

X12 is His, Phe, Arg, N-Me-His, Val, D-His, Cav, Cpa, Leu, Cit, hLeu,3-Pal, t-butyl-Ala, t-butyl-Gly, 4-amino-4-carboxy-tetrahydropyran, AchcAcpc, Acbc, Acvc, Agp, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac),α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D)Asn, Glu, hArg,or Lys;X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, βhAla, Aib, Lys(Ac),Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln;X14 is Phe, Tyr, βhPhe, Asn, Arg, Gln, Lys(Ac), His; Dap(Ac), Dab(Ac) orAsp or absent;X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn or absent;X16 is any amino acid or absent;X17 is any amino acid or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent.

In particular embodiments of Ik: X5 is Ala, Arg, Glu, Phe, Leu, Thr,Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib,or D-Sarc; X10 is Tyr or Phe; X11 is Trp, 1-Nal, or 2-Nal; X12 is His,Phe, Arg, N-Me-His, Val, D-His, Cav, Cpa, Leu, Cit, hLeu, 3-Pal,t-butyl-Ala, or t-butyl-Gly; X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys,Val, βhAla, Aib or absent; X14 is Phe, Tyr, βhPhe or absent; X15 is Gly,Ser, Thr, Gln, Ala, Sarc or absent; X16 is Asp, Glu, Ala, AEA, AEP,βhAla, Gaba, Leu, or absent; and X17 is Leu, Lys, Arg, or absent.

In certain embodiments of Formula I, X comprises or consists of thesequence of Formula Il:

X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (Il),

wherein

X1 is any amino acid or absent;X2 is any amino acid or absent;X3 is any amino acid or absent;X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, Asp, Lys, Orn,Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys or absent;

X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, α-MeOrn, α-MeSer,Cit, Dap, Dab, Dap(Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn or Gln; X6is Asp, Thr, Asn, or Phe; X8 is Val, Gln, Glu, or Lys;

X9 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab,D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Asp, Leu, Val, Phe, or Ser;X10 is Tyr, Phe, Phe(3,4-F₂), Phe(3,4-Cl₂), F(3-Me),Phe[4-(2-aminoethoxy)], Phe[4-(2-(acetyl-aminoethoxy)], Phe(4-Br),Phe(4-CONH₂), Phe(4-C1), Phe(4-CN), Phe(4-guanidino), Phe(4-Me),Phe(4-NH₂), Phe(4-N₃), Phe(4-OMe), Phe(4-OBzl) or Tyr;X11 is Trp, 1-Nal, 2-Nal, Phe(3,4-OMe₂) 5-Hydroxy-Trp, Phe(3,4-Cl₂) orTyr(3-t-Bu);X12 is His, Phe, Arg, N-Me-His, Val, D-His, Cav, Cpa, Leu, Cit, hLeu,3-Pal, t-butyl-Ala, t-butyl-Gly, 4-amino-4-carboxy-tetrahydropyran, AchcAcpc, Acbc, Acvc, Agp, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac),α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D)Asn, Glu, hArg,or Lys;X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, βhAla, Aib, Lys(Ac),Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln or absent;X14 is Phe, Tyr, βhPhe, Asn, Arg, Gln, Lys(Ac), His; Dap(Ac), Dab(Ac) orAsp or absent;X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn or absent;X16 is any amino acid or absent;X17 is any amino acid or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent.

In particular embodiments of Il: X5 is Ala, Arg, Glu, Phe, Leu, Thr,Ser, Aib, or Sarc; X10 is Tyr or Phe; X11 is Trp, 1-Nal, or 2-Nal; X12is His, Phe, Arg, N-Me-His, Val, D-His, Cav, Cpa, Leu, Cit, hLeu, 3-Pal,t-butyl-Ala, or t-butyl-Gly; X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys,Val, βhAla, Aib or absent; X14 is Phe, Tyr, βhPhe or absent; X15 is Gly,Ser, Thr, Gln, Ala, Sarc or absent; X16 is Asp, Glu, Ala, AEA, AEP,βhAla, Gaba, Leu, or absent; and X17 is Leu, Lys, Arg, or absent.

In certain embodiments, X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys,βhAla, Aib, Lys(Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, orGln. In certain embodiments, X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys,βhAla, or Aib.

In certain embodiments, X14 is Phe, Tyr, βhPhe, Asn, Arg, Gln, Lys(Ac),His; Dap(Ac), Dab(Ac) or Asp. In certain embodiments, X14 is Phe, Tyr,or βhPhe.

In certain embodiments, X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala,Glu, Arg or Asn. In certain embodiments, X15 is Gly, Ser, Thr, Gln, Ala,or Sarc.

In certain embodiments, X12 is alpha amino acid, e.g.,4-amino-4-carboxy-tetrahydropyran, Achc Acpc, Acbc, Aib,α-MeGly(diethyl), α-MeLys, α-MeLys(Ac), α-Me-Leu, α-MeOrn, α-MeSer,α-MeVal.

In certain embodiments, X13 is present.

In certain embodiments, X13 and X14 are present.

In certain embodiments, X13, X14 and X15 are present.

In particular embodiments, X4 is present.

In certain embodiments, the peptide inhibitor is cyclized.

In certain embodiments, the peptide inhibitor is linear or not cyclized.

In certain embodiments, the peptide inhibitor is cyclized, or containsan intramolecular bond, between X4 and X9.

In certain embodiments of the peptide inhibitor of Formula I, Xcomprises or consists of the sequence of Formula Im:

X1-X2-X3-X4-X5-X6-W-X8-X9-Y-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (Im),

wherein

X1 is any amino acid or absent;X2 is any amino acid or absent;X3 is any amino acid or absent;X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, Asp, Lys, Orn,Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys or absent;

X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, α-MeOrn, α-MeSer,Cit, Dap, Dab, Dap(Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn, or Gln; X6is Asp, Thr, Asn, or Phe; X8 is Val, Gln, Glu, or Lys;

X9 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab,D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Asp, Leu, Val, Phe, or Ser;X11 is Trp, 1-Nal, 2-Nal, Phe(3,4-OMe₂); 5-Hydroxy-Trp, Phe(3,4-Cl₂), orTyr(3-t-Bu);X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal,t-butyl-Ala, or t-butyl-Gly, 4-amino-4-carboxy-tetrahydropyran, AchcAcpc, Acbc, Acvc, Agp, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac),α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D)Asn, Glu, hArg,or Lys;X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, βhAla, Val, Aib, Lys(Ac),Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln or absent;X14 is Phe, Tyr, βhPhe, Asn, Arg, Gln, Lys(Ac), His; Dap(Ac), Dab(Ac),or Asp or absent;X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn or absent;X16 is any amino acid or absent;X17 is any amino acid or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent.

In certain embodiments of Im: X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser,Aib, or Sarc; X11 is Trp, 1-Nal, or 2-Nal; X12 is His, Phe, Arg,N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, ort-butyl-Gly; X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, βhAla, Val, Aibor absent; X14 is Phe, Tyr, βhPhe or absent; X15 is Gly, Ser, Thr, Gln,Ala, Sarc or absent; X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba, orabsent; and X17 is Leu, Lys, Arg, or absent.

In certain embodiments, X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys,βhAla, or Aib. In certain embodiments, X13 is Thr, Sarc, Glu, Phe, Arg,Leu, Lys, βhAla, Aib, Lys(Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn,Orn, or Gln.

In certain embodiments, X14 is Phe, Tyr, βhPhe, Asn, Arg, Gln, Lys(Ac),His; Dap(Ac), Dab(Ac) or Asp. In certain embodiments, X14 is Phe, Tyr,or βhPhe.

In certain embodiments, X15 is Gly, Ser, Thr, Gln, Ala, or Sarc, β-Ala,Glu, Arg or Asn. In certain embodiments, X15 is Gly, Ser, Thr, Gln, Ala,or Sarc.

In certain embodiments, X12 is alpha amino acid, e.g.,4-amino-4-carboxy-tetrahydropyran, Achc Acpc, Acbc, Aib,α-MeGly(diethyl), α-MeLys, α-MeLys(Ac), α-Me-Leu, α-MeOrn, α-MeSer,α-MeVal.

In certain embodiments, X13 is present.

In certain embodiments, X13 and X14 are present.

In certain embodiments, X13, X14, and X15 are present.

In particular embodiments, X4 is present.

In certain embodiments, the peptide inhibitor is cyclized.

In certain embodiments, the peptide inhibitor is linear or not cyclized.

In certain embodiments, the peptide inhibitor is cyclized, or containsan intramolecular bond, between X4 and X9.

In certain embodiments of the peptide inhibitor of Formula I, Xcomprises or consists of the sequence of Formula In:

X1-X2-X3-C-X5-X6-W-X8-C-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (In)

wherein

X1 is any amino acid or absent;X2 is any amino acid or absent;X3 is any amino acid or absent;

X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, α-MeOrn, α-MeSer,Cit, Dap, Dab, Dap(Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn or Gln; X6is Asp, Thr, Asn, or Phe; X8 is Val, Gln, Glu, or Lys;

X10 is Tyr Phe, Phe(3,4-F₂), Phe(3,4-Cl₂), F(3-Me),Phe[4-(2-aminoethoxy)], Phe[4-(2-(acetyl-aminoethoxy)], Phe(4-Br),Phe(4-CONH₂), Phe(4-Cl), Phe(4-CN), Phe(4-guanidino), Phe(4-Me),Phe(4-NH₂), Phe(4-N₃), Phe(4-OMe), Phe(4-OBzl) or Tyr;X11 is Trp, 1-Nal, 2-Nal, Phe(3,4-OMe₂) 5-Hydroxy-Trp, Phe(3,4-Cl₂) orTyr(3-t-Bu);X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal,t-butyl-Ala, or t-butyl-Gly, 4-amino-4-carboxy-tetrahydropyran, AchcAcpc, Acbc, Acvc, Agp, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac),α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D)Asn, Glu, hArg,or Lys;X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, βhAla, Val, Aib, Lys(Ac),Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln or absent;X14 is Phe, Tyr, βhPhe, Asn, Arg, Gln, Lys(Ac), His; Dap(Ac), Dab(Ac) orAsp or absent;X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn or absent;X16 is any amino acid or absent;X17 is any amino acid or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent,

wherein the Cys at position X4 and and the Cys at position X9 areoptionally linked by a disulphide bridge.

In certain embodiments of In: X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser,Aib, Sarc, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap(Ac), Gly, Lys, Asn,N-MeGln, N-MeArg, Orn or Gln; X10 is Tyr, Phe, Phe(3,4-F₂),Phe(3,4-Cl₂), F(3-Me), Phe[4-(2-aminoethoxy)],Phe[4-(2-(acetyl-aminoethoxy)], Phe(4-Br), Phe(4-CONH₂), Phe(4-Cl),Phe(4-CN), Phe(4-guanidino), Phe(4-Me), Phe(4-NH₂), Phe(4-N₃),Phe(4-OMe), Phe(4-OBzl) or Tyr; X11 is Trp, 1-Nal, 2-Nal, Phe(3,4—OMe₂)5-Hydroxy-Trp, Phe(3,4-Cl₂) or Tyr(3-t-Bu); X12 is His, Phe, Arg,N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, ort-butyl-Gly, 4-amino-4-carboxy-tetrahydropyran, Achc Acpc, Acbc, Acvc,Agp, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac), α-Me-Leu, α-MeOrn,α-MeSer, α-MeVal, Cha, Cit, Cpa, (D)Asn, Glu, hArg, or Lys; X13 is Thr,Sarc, Glu, Phe, Arg, Leu, Lys, βhAla, Val, Aib, Lys(Ac), Cit, Asp, Dab,Dap, Glu, hArg, Lys, Asn, Orn, or Gln or absent; X14 is Phe, Tyr, βhPhe,Asn, Arg, Gln, Lys(Ac), His; Dap(Ac), Dab(Ac) or Asp or absent; X15 isGly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn or absent; X16 isAsp, Glu, Ala, AEA, AEP, βhAla, Gaba, or absent; and X17 is Leu, Lys,Arg, or absent.

In certain embodiments, X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys,βhAla, Aib, Lys(Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, orGln. In certain embodiments, X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys,βhAla, or Aib.

In certain embodiments, X14 is Phe, Tyr, βhPhe, Asn, Arg, Gln, Lys(Ac),His; Dap(Ac), Dab(Ac) or Asp. In certain embodiments, X14 is Phe, Tyr,or βhPhe.

In certain embodiments, X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala,Glu, Arg or Asn. In certain embodiments, X15 is Gly, Ser, Thr, Gln, Ala,or Sarc.

In certain embodiments, X12 is an alpha amino acid, e.g.,4-amino-4-carboxy-tetrahydropyran, Achc Acpc, Acbc, Acvc, Aib,α-DiethylGly, α-MeLys, α-MeLys(Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal.

In certain embodiments, X13 is present.

In certain embodiments, X13 and X14 are present.

In certain embodiments, X13, X14 and X15 are present.

In certain embodiments of the peptide inhibitor of Formula I, Xcomprises or consists of the sequence of Formula Io:

(SEQ ID NO: 1112) X1-X2-X3-C-X5-X6-W-X8-C-Y-X11-H-X13-X14-X15-X16-X17-X18-X19-X20 (Io)

wherein

X1 is any amino acid or absent;X2 is any amino acid or absent;X3 is any amino acid or absent;

X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, α-MeOrn, α-MeSer,Cit, Dap, Dab, Dap(Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn or Gln; X6is Asp, Thr, Asn, or Phe; X8 is Val, Gln, Glu, or Lys;

X11 is Trp, 1-Nal, 2-Nal, Phe(3,4-OMe₂) 5-Hydroxy-Trp, Phe(3,4-Cl₂) orTyr(3-t-Bu);X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, βhAla, Val, Aib, Lys(Ac),Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln or absent;X14 is Phe, Tyr, Asn, Arg, Gln, Lys(Ac), His; Dap(Ac), Dab(Ac) or Asp orabsent;X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn or absent;X16 is any amino acid or absent;X17 is any amino acid or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent,

wherein the Cys at position X4 and and the Cys at position X9 areoptionally linked by a disulphide bridge.

In certain embodiments of Io: X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser,Aib, Sarc, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap(Ac), Gly, Lys, Asn,N-MeGln, N-MeArg, Orn or Gln; X11 is Trp, 1-Nal, 2-Nal, Phe(3,4-OMe₂),5-Hydroxy-Trp, Phe(3,4-Cl₂) or Tyr(3-t-Bu); X13 is Thr, Sarc, Glu, Phe,Arg, Leu, Lys, βhAla, Val, Aib, Lys(Ac), Cit, Asp, Dab, Dap, Glu, hArg,Lys, Asn, Orn, Gln or absent; X14 is Phe, Tyr, Asn, Arg, Gln, Lys(Ac),His; Dap(Ac), Dab(Ac) Asp or absent; X15 is Gly, Ser, Thr, Gln, Ala,Sarc, β-Ala, Glu, Arg or Asn or absent; X16 is Asp, Glu, Glu, Ala, AEA,AEP, βhAla, Gaba, or absent; and X17 is Leu, Lys, Arg, or absent.

In certain embodiments, X12 is an alpha amino acid, e.g.,4-amino-4-carboxy-tetrahydropyran, Achc Acpc, Acbc, Acvc, Aib,α-DiethylGly, α-MeLys, α-MeLys(Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal.

In certain embodiments, X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys,βhAla, Aib, Lys(Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, orGln. In certain embodiments, X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys,βhAla or Aib.

In certain embodiments, X14 is Phe, Tyr, Asn, Arg, Gln, Lys(Ac), His;Dap(Ac), Dab(Ac) or Asp. In certain embodiments, X14 is Phe or Tyr.

In certain embodiments, X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala,Glu, Arg or Asn. In certain embodiments, X15 is Gly, Ser, Thr, Gln, Alaor Sarc.

In certain embodiments, X13 is present.

In certain embodiments, X13 and X14 are present.

In certain embodiments, X13, X14 and X15 are present.

In certain embodiments of the peptide inhibitor of Formula I, Xcomprises or consists of the sequence of Formula Ip:

(SEQ ID NO: 1113) X1-X2-X3-C-X5-X6-W-X8-C-Y-X11-H-X13-F-X15-X16-X17-X18-X19-X20 (Ip)

wherein

X1 is any amino acid or absent;X2 is any amino acid or absent;X3 is any amino acid or absent;

X5 is Ala, Arg, Sarc, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap(Ac), Gly,Lys, Asn, N-MeGln, N-MeArg, Orn or Gln; X6 is Asp, Thr, or Asn; X8 isVal, Gln, or Glu;

X11 is Trp, 1-Nal, 2-Nal, Phe(3,4-OMe₂) 5-Hydroxy-Trp, Phe(3,4-Cl₂) orTyr(3-t-Bu);X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, βhAla, Val, Aib, Lys(Ac),Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, Gln or absent;X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg Asn or absent;X16 is any amino acid or absent;X17 is any amino acid or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent,

wherein the Cys at position X4 and and the Cys at position X9 areoptionally linked by a disulphide bridge.

In certain embodiments of Ip: X5 is Ala, Arg, or Sarc; X11 is Trp,1-Nal, or 2-Nal; X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, βhAla, Val,Aib or absent; X15 is Gly, Ser, Thr, Gln, Ala, Sarc or absent; X16 isAsp, Glu, Ala, AEA, AEP, βhAla, Gaba, or absent; and X17 is Leu, Lys,Arg, or absent.

In certain embodiments, X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys,βhAla, Aib, Lys(Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, orGln. In certain embodiments, X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys,βhAla or Aib.

In certain embodiments, X15 is Gly, Ser, Thr, Gln, Ala or Sarc, Glu, Argor Asn. In certain embodiments, X15 is Gly, Ser, Thr, Gln, Ala or Sarc.

In certain embodiments, X13 is present.

In certain embodiments, X13 and X14 are present.

In certain embodiments, X13, X14 and X15 are present.

In certain embodiments of the peptide inhibitor of Formula I, Xcomprises or consists of the sequence of Formula Iq:

X1-X2-X3-C-X5-X6-W-X8-C-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (Iq),

whereinX1 is any amino acid or absent;X2 is any amino acid or absent;X3 is any amino acid or absent;

X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu,D-Phe, D-Leu, D-Thr, D-Ser, D-Aib, D-Sarc, α-MeOrn, α-MeSer, Cit, Dap,Dab, Dap(Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn or Gln; X6 is Asp,Thr, Asn, Phe, D-Asp, D-Thr, D-Asn, or D-Phe; X8 is Val, Gln, Glu, orLys;

X10 is Tyr, Phe, Phe(3,4-F₂), Phe(3,4-Cl₂), F(3-Me),Phe[4-(2-aminoethoxy)], Phe[4-(2-(acetyl-aminoethoxy)], Phe(4-Br),Phe(4-CONH₂), Phe(4-Cl), Phe(4-CN), Phe(4-guanidino), Phe(4-Me),Phe(4-NH₂), Phe(4-N₃), Phe(4-OMe), Phe(4-OBzl) or Tyr;X11 is Trp, 1-Nal, 2-Nal, Phe(3,4-OMe₂) 5-Hydroxy-Trp, Phe(3,4-Cl₂) orTyr(3-t-Bu);X12 is His, Phe, Arg, N-Me-His, Val, or D-His, Cav, Cpa, Leu, Cit, hLeu,3-Pal, t-butyl-Ala, t-butyl-Gly, 4-amino-4-carboxy-tetrahydropyran, AchcAcpc, Acbc, Acvc, Agp, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac),α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D)Asn, Glu, hArg,or Lys;X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, βhAla, Val, Aib, Lys(Ac),Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, Gln or absent;X14 is Phe, Tyr, βhPhe, Asn, Arg, Gln, Lys(Ac), His; Dap(Ac), Dab(Ac),Asp or absent;X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg, Asn or absent;X16 is any amino acid or absent;X17 is any amino acid or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent,

wherein the Cys at position X4 and and the Cys at position X9 areoptionally linked.

In certain embodiments of Iq: X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser,Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib, orD-Sarc; X10 is Tyr or Phe; X11 is Trp, 1-Nal, or 2-Nal; X12 is His, Phe,Arg, N-Me-His, Val, or D-His, Cav, Cpa, Leu, Cit, hLeu, 3-Pal,t-butyl-Ala, or t-butyl-Gly; X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys,βhAla, Val, Aib or absent; X14 is Phe, Tyr, βhPhe or absent; X15 is Gly,Ser, Thr, Gln, Ala, Sarc or absent; X16 is Asp, Glu, Ala, AEA, AEP,βhAla, Gaba, Leu, or absent; and X17 is Leu, Lys, Arg, or absent.

In certain embodiments, X12 is alpha amino acid, e.g.,4-amino-4-carboxy-tetrahydropyran, Achc Acpc, Acbc, Acvc, Aib,α-DiethylGly, α-MeLys, α-MeLys(Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal.

In certain embodiments, X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys,βhAla, Aib, Lys(Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, orGln. In certain embodiments, X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys,βhAla or Aib.

In certain embodiments, X14 is Phe, Tyr, βhPhe, Asn, Arg, Gln, Lys(Ac),His; Dap(Ac), Dab(Ac), or Asp. In certain embodiments, X14 is Phe, Tyror βhPhe.

In certain embodiments, X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala,Glu, Arg or Asn. In certain embodiments, X15 is Gly, Ser, Thr, Gln, Alaor Sarc.

In certain embodiments, X13 is present.

In certain embodiments, X13 and X14 are present.

In certain embodiments, X13, X14 and X15 are present.

In certain embodiments, Iq comprises or consists of the sequence ofFormula Iq′:

X1-X2-X3-C-X5-X6-W-X8-C-X10-X11-X12-X13-X14-X15  (Iq′),

wherein X1-X14 have the definition provided for Iq, andwherein the Cys at position X4 and and the Cys at position X9 areoptionally linked.

In certain embodiments of Iq′: X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser,Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib, orD-Sarc; X10 is Tyr or Phe; X11 is Trp, 1-Nal, or 2-Nal; X12 is His, Phe,Arg, N-Me-His, Val, or D-His, Cav, Cpa, Leu, Cit, hLeu, 3-Pal,t-butyl-Ala, or t-butyl-Gly; X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys,βhAla, Val, Aib or absent; X14 is Phe, Tyr, βhPhe or absent; X15 is Gly,Ser, Thr, Gln, Ala, Sarc or absent; X16 is Asp, Glu, Ala, AEA, AEP,βhAla, Gaba, Leu, or absent; and X17 is Leu, Lys, Arg, or absent.

In certain embodiments, X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys,βhAla, Aib, Lys(Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, orGln. In certain embodiments, X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys,βhAla or Aib.

In certain embodiments, X14 is Phe, Tyr, βhPhe, Asn, Arg, Gln, Lys(Ac),His; Dap(Ac), Dab(Ac) or Asp. In certain embodiments, X14 is Phe, Tyr orβhPhe.

In certain embodiments, X15 is Gly, Ser, Thr, Gln, Ala or Sarc, β-Ala,Glu, Arg or Asn. In certain embodiments, X14 is Phe, Tyr or βhPhe.

In certain embodiments, X13 is present.

In certain embodiments, X13 and X14 are present.

In certain embodiments, X13, X14 and X15 are present.

In certain embodiments of the peptide inhibitor of Formula I, Xcomprises or consists of the sequence of Formula Ir:

X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (Ir)

whereinX1 is any amino acid or absent;X2 is any amino acid or absent;X3 is any amino acid or absent;X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, Asp, Lys, Orn,Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Sec, 2-chloromethylbenzoicacid, mercapto-propanoic acid, mercapto-butyric acid, 2-chloro-aceticacid, 3-choro-propanoic acid, 4-chloro-butyric acid, 3-chloro-isobutyricacid, Abu, β-azido-Ala-OH, propargylglycine, 2-(3′-butenyl)glycine,2-allylglycine, 2-(3′-butenyl)glycine, 2-(4′-pentenyl)glycine,2-(5′-hexenyl)glycine, Abu or absent;X5 is any amino acid;X6 is any amino acid;X7 is Trp, Glu, Gly, Ile, Asn, Pro, Arg, Thr or OctGly, or acorresponding α-methyl amino acid form of any of the foregoing;X8 is any amino acid;X9 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab,D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Asp, Leu, Val, Phe, or Ser, Sec, Abu,β-azido-Ala-OH, propargylglycine, 2-2-allylglycine,2-(3′-butenyl)glycine, 2-(4′-pentenyl)glycine, Ala, hCys, Abu, Met,MeCys, (D)Tyr or 2-(5′-hexenyl)glycine;X10 is Tyr, Phe(4-OMe), 1-Nal, 2-Nal, Aic, α-MePhe, Bip, (D)Cys, Cha,DMT, (D)Tyr, Glu, His, hPhe(3,4-dimethoxy), hTyr, N-Me-Tyr, Trp,Phe(4-CONH₂), Phe(4-phenoxy), Thr, Tic, Tyr(3-tBu), Phe(4-tBu),Phe(4-CN), Phe(4-Br), Phe(4-NH₂), Phe(4-F), Phe(3,5-F₂), Phe(4-CH₂CO₂H),Phe(penta-F), Phe(3,4-Cl₂), Phe(4-CF₃), Bip, Cha, 4-PyridylAlanine,βhTyr, OctGly, Phe(4-N₃), Phe(4-Br), Phe[4-(2-aminoethoxy)] or Phe, aPhe analog, a Tyr analog, or a corresponding α-methyl amino acid form ofany of the foregoing;X11 is 2-Nal, 1-Nal, 2,4-dimethylPhe, Bip, Phe(3,4-Cl₂), Phe (3,4-F₂),Phe(4-CO₂H), βhPhe(4-F), α-Me-Trp, 4-phenylcyclohexyl, Phe(4-CF₃),Phe(3,4-OMe₂), α-MePhe, βhNal, βhPhe, βhTyr, βhTrp, Nva(5-phenyl), Phe,His, hPhe, Tic, Tqa, Trp, Tyr, Phe(4-OMe), Phe(4-Me),Trp(2,5,7-tri-tert-Butyl), Phe(4-Oallyl), Tyr(3-tBu), Phe(4-tBu),Phe(4-guanidino, Phe(4-OBzl), Octgly, Glu(Bzl), 4-Phenylbenzylalanine,Phe[4-(2-aminoethoxy)], 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp,1,2,3,4-tetrahydro-norharman, Phe(4-CONH₂), Phe(3,4-Dimethoxy),Phe(2,3-C12), Phe(2,3-F₂), Phe(4-F), 4-phenylcyclohexylalanine or Bip,or a corresponding α-methyl amino acid form of any of the foregoing;X12 is His, Phe, Arg, N-Me-His, or Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal,t-butyl-Ala, α-MeLys, D-Ala, (D)Asn, (D)Asp, (D)Leu, (D)Phe, (D)Tyr,Aib, α-MeLeu, α-MeOrn, β-Aib, β-Ala, βhAla, βhArg, βhLeu, βhVal,β-spiro-pip, Glu, hArg, Ile, Lys, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln,Ser, Thr, Tle or t-butyl-Gly, 4-amino-4-carboxy-tetrahydropyran, AchcAcpc, Acbc, Acvc, Agp, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac),α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D)Asn, Glu, hArg,or Lys or a corresponding α-methyl amino acid form of any of theforegoing;X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Asn, Cit, Lys, Arg, Orn, Val,βhAla, Lys(Ac), (D)Asn, (D)Leu, (D)Phe, (D)Thr, Ala, α-MeLeu, Aib,β-Ala, β-Glu, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Dab, Dap,α-DiethylGly, hLeu, Asn, Ogl, Pro, Gln, Ser, β-spiro-pip, Thr, Tba, Tleor Aib, or a corresponding α-methyl amino acid form of any of theforegoing;X14 is Phe, Tyr, Glu, Gly, His, Lys, Leu, Met, Asn, Lys(Ac), Dap(Ac),Asp, Pro, Gln, Arg, Ser, Thr, Tic or βhPhe, or a corresponding α-methylamino acid form of any of the foregoing;X15 is Gly, Ser, Thr, Gln, Ala, (D)Ala, (D)Asn, (D)Asp, (D)Leu, (D)Phe,(D)Thr, Aea, Asp, Asn, Glu, Phe, Gly, Lys, Leu, Pro, Arg, β-Ala, orSarc, or a corresponding α-methyl amino acid form of any of theforegoing;X16 is any amino acid or absent;X17 is any amino acid or absent;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent.

In particular embodiments, the peptide is cyclized via X4 and X9.

In particular embodiments, X3 is Glu, D-Glu, Arg, (D)Arg, Phe, (D)Phe,2-Nal, Thr, Leu, (D)Gln.

In certain embodiments of Ir: X11 is 2-Nal, 1-Nal, 2,4-dimethylPhe, Bip,Phe(3,4-Cl₂), Phe (3,4-F₂), Phe(4-CO₂H), βhPhe(4-F), α-Me-Trp,4-phenylcyclohexyl, Phe(4-CF₃), α-MePhe, βhPhe, βhTyr, βhTrp,Nva(5-phenyl), Phe, His, hPhe, Tic, Tqa, Trp, Tyr, Phe(4-OMe),Phe(4-Me), Trp(2,5,7-tri-tert-Butyl), Phe(4-Oallyl), Tyr(3-tBu),Phe(4-tBu), Phe(4-guanidino, Phe(4-OBzl), Octgly, Glu(Bzl),4-Phenylbenzylalanine, Phe[4-(2-aminoethoxy)], 5-Hydroxy-Trp,6-Chloro-Trp, N-MeTrp, 1,2,3,4-tetrahydro-norharman, Phe(4-CONH₂),Phe(3,4-Dimethoxy), Phe(2,3-Cl₂), Phe(2,3-F₂), Phe(4-F),4-phenylcyclohexylalanine or Bip, or a corresponding α-methyl amino acidform of any of the foregoing; X12 is His, Phe, Arg, N-Me-His, or Val,Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, α-MeLys, D-Ala, (D)Asn,(D)Asp, (D)Leu, (D)Phe, (D)Tyr, Aib, α-MeLeu, α-MeOrn, β-Ala, βhAla,βhArg, βhLeu, βhVal, 3-spiro-pip, Glu, hArg, Ile, Lys, N-MeLeu, N-MeArg,Ogl, Orn, Pro, Gln, Ser, Thr, Tle or t-butyl-Gly, or a correspondingα-methyl amino acid form of any of the foregoing; X13 is Thr, Sarc, Glu,Phe, Arg, Leu, Lys, Arg, Orn, Val, βhAla, Lys(Ac), (D)Asn, (D)Leu,(D)Phe, (D)Thr, Ala, α-MeLeu, Aib, β-Ala, β-Glu, βhLeu, βhVal,β-spiro-pip, Cha, Chg, Asp, Dab, Dap, α-DiethylGly, hLeu, Asn, Ogl, Pro,Gln, Ser, β-spiro-pip, Thr, Tba, Tle or Aib, or a corresponding α-methylamino acid form of any of the foregoing; X14 is Phe, Tyr, Glu, Gly, His,Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic or βhPhe, or acorresponding α-methyl amino acid form of any of the foregoing; X15 isGly, Ser, Thr, Gln, Ala, (D)Ala, (D)Asn, (D)Asp, (D)Leu, (D)Phe, (D)Thr,Aea, Asp, Asn, Glu, Phe, Gly, Lys, Leu, Pro, Arg or Sarc, or acorresponding α-methyl amino acid form of any of the foregoing; X16 isAsp, Glu, Ala, AEA, AEP, βhAla, Gaba, Gly, Ser, Pro, Asn, Thr or absent,or a corresponding α-methyl amino acid form of any of the foregoing; andX17 is Leu, Lys, Arg, Glu, Ser, Gly, Gln or absent, or a correspondingα-methyl amino acid form of any of the foregoing.

In certain embodiments, both X4 and X9 are Pen. In particularembodiments, X4 and X9 are cyclized via a disulfide bond.

In certain embodiments, X4 is Abu and X9 is Cys. In certain embodiments,X4 and X9 are cyclized via a thioether bond.

In particular embodiments, X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib,Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib, Cys, Cit,Asp, Dab, Dap, Gly, His, hCys, Lys, Met, Asn, N-Me-Ala, N-Me-Asn,N-Me-Lys, N-Me-Gln, Orn, Pro, Pen, Gln, Val, αMe-Lys, αMe-Orn, orD-Sarc, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap(Ac), Gly, Lys, Asn,N-MeGln, N-MeArg, or Gln. In certain embodiments, X5 is Gln or Asn. Inparticular embodiments, X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib,Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib, Cys, Cit,Asp, Dab, Dap, Gly, His, hCys, Lys, Met, Asn, N-Me-Ala, N-Me-Asn,N-Me-Lys, N-Me-Gln, N-Me-Arg, Orn, Pro, Pen, Gln, Val, αMe-Lys, αMe-Orn,or D-Sarc. In certain embodiments, X5 is Gln.

In particular embodiments, X6 is Asp, Thr, Asn, Phe, D-Asp, D-Thr,D-Asn, Glu, Arg, Ser or D-Phe. In particular embodiments, X6 is Thr.

In particular embodiments, X7 is Trp.

In particular embodiments, X8 is Val, Gln, Glu, Phe, Asn, Pro, Arg, Thr,Trp or Lys. In particular embodiments, X8 is Gln.

In particular embodiments, X1, X2 and X3 are absent.

In certain embodiments, X11 is a Trp analog.

In particular embodiments, X10 is a Phe analog. In particularembodiments, X10 is Phe(4-OMe), Phe(4-CONH₂), or Phe[4-(2-aminoethoxy)](also referred to herein as Phe[4-2ae)]). In particular embodiments, X10is Phe(4-OMe) or Phe[4-(2-aminoethoxy)] (also referred to herein asPhe[4-2ae)]).

In particular embodiments, X11 is 2-Nal or 1-Nal. In certainembodiments, X11 is 2-Nal.

In certain embodiments, X12 is α-MeLys,4-amino-4-carboxy-tetrahydropyran, Achc Acpc, Acbc, Acvc, Agp, Aib,α-DiethylGly, α-MeLys, α-MeLys(Ac), α-Me-Leu, α-MeOrn, α-MeSer, orα-MeVal. In certain embodiments, X12 is α-MeLys.

In certain embodiments, X13 is Glu or Lys(Ac). In certain embodiments,X13 is Glu.

In certain embodiments, X14 is Asn.

In certain embodiments, X15 is Gly or Asn. In certain embodiments, X15is Gly.

In certain embodiments, one or more, two or more, three or more, or fouror more of X16, X17, X18, X19 and X20 are absent. In particularembodiments, X16, X17, X18, X19 and X20 are absent.

In particular embodiments of Ir, X4 and X9 are Cys, X7 is Trp, and X18is [(D)Lys]. In particular embodiments of Ir, X4 and X9 are Cys, X7 isTrp, X10 is Tyr, and X18 is [(D)Lys]. In particular embodiments of Ir,X4 and X9 are Cys, X7 is Trp, X1, X2 and X3 are absent, X17 is absent,X18 is [(D)Lys], and X19 and X20 are absent. In particular embodimentsof Ir, X4 and X9 are Cys, X7 and X11 are Trp, X10 is Tyr, and X18 is[(D)Lys. In certain embodiments, X1, X2, and X3 are absent; and incertain embodiments, X17 is absent.

In particular embodiments of Ir, X4 and X9 are Pen, and X12 is α-MeLys.In particular embodiments of Ir, X4 and X9 are Pen, X12 is α-MeLys, andX16, X17, X18, X19 and X20 are absent. In particular embodiments of Ir,X4 and X9 are Pen, X12 is α-MeLys, 4-amino-4-carboxy-tetrahydropyran,Achc Acpc, Acbc, Acvc, Agp, Aib, α-DiethylGly, α-MeLys(Ac), α-Me-Leu,α-MeOrn, α-MeSer, α-MeVal, X16, X17, X18, X19 and X20 are absent, and X7is Trp. In particular embodiments of Ir, X4 and X9 are Pen, X12 isα-MeLys, X16, X17, X18, X19 and X20 are absent, and X7 is Trp. Inparticular embodiments of Ir, X4 and X9 are Pen, X7 is Trp, and X12 isα-MeLys. In certain embodiments, X1, X2, and X3 are absent. Inparticular embodiments, there is a disulfide bond between X4 and X9.

In particular embodiments of Ir, X4 is Abu, X9 is Cys, and X12 is4-amino-4-carboxy-tetrahydropyran, Achc Acpc, Acbc, Acvc, Agp, Aib,α-DiethylGly, α-MeLys, or α-MeLys(Ac), α-Me-Leu, α-MeOrn, α-MeSer, orα-MeVal. In particular embodiments of Ir, X4 is Abu, X9 is Cys, and X12is α-MeLys. In particular embodiments of Ir, X4 is Abu, X9 is Cys, X12is α-MeLys, 4-amino-4-carboxy-tetrahydropyran, Achc Acpc, Acbc, Acvc,Agp, Aib, α-DiethylGly, α-MeLys, or α-MeLys(Ac), α-Me-Leu, α-MeOrn,α-MeSer, or α-MeVal and X16, X17, X18, X19 and X20 are absent. Inparticular embodiments of Ir, X4 is Abu, X9 is Cys, X12 is α-MeLys, andX16, X17, X18, X19 and X20 are absent. In particular embodiments of Ir,X4 is Abu, X9 is Cys, X12 is α-MeLys, 4-amino-4-carboxy-tetrahydropyran,Achc Acpc, Acbc, Acvc, Agp, Aib, α-DiethylGly, α-MeLys, or α-MeLys(Ac),α-Me-Leu, α-MeOrn, α-MeSer, or α-MeVal, X16, X17, X18, X19 and X20 areabsent, and X7 is Trp. In particular embodiments of Ir, X4 is Abu, X9 isCys, X12 is α-MeLys, X16, X17, X18, X19 and X20 are absent, and X7 isTrp. In particular embodiments of Ir, X4 is Abu, X9 is Cys, X7 is Trp,and X12 is α-MeLys. In certain embodiments, X1, X2, and X3 are absent.In particular embodiments, there is a thioether bond between X4 and X9.

In certain embodiments of the peptide inhibitor of Formula I, Xcomprises or consists of the sequence of Formula Is:

(SEQ ID NO: 1114) X1-X2-X3-C-X5-X6-W-X8-C-X10-X11-X12-X13-X14-G-X16-X17-X18-X19-X20 (Is)whereinX1 is any amino acid or absent;X2 is any amino acid or absent;X3 is any amino acid or absent;X5 is any amino acid;X6 is any amino acid;X8 is any amino acid;X10 is Tyr, 1-Nal 2-Nal, Phe(3,4-F₂), Phe(3,4-Cl₂), F(3-Me),Phe[4-(2-aminoethoxy)], Phe[4-(2-(acetyl-aminoethoxy)], Phe(4-Br),Phe(4-CONH₂), Phe(4-Cl), Phe(4-CN), Phe(4-guanidino), Phe(4-Me),Phe(4-NH₂), Phe(4-N₃), Phe(4-OMe), Phe(4-OBzl) or Tyr;X11 is Trp 1-Nal, Phe(3,4-OMe₂) 5-Hydroxy-Trp, Phe(3,4-Cl₂) orTyr(3-t-Bu);X12 is Arg, Lys, His, hArg, Cit, Orn, 1-Nal, D-Ala, D-Leu, D-Phe, D-Asn,D-Asp, Agp, Leu, βhLeu, Aib, βhAla, βhVal, βhArg, hLeu, Dap,4-amino-4-carboxy-tetrahydropyran, Achc Acpc, Acbc, Acvc, Agp, Aib,α-DiethylGly, α-MeLys, α-MeLys(Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal,Cha, Cit, Cpa, (D)Asn, Glu, hArg, or Lys;X13 is Cha, Ogl, Aib, Leu, Val, Dab, Glu, Lys, βhLeu, βhAla, βhVal βGlu,Lys(Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, Lys(Ac), or Gln;

X14 is Phe, Tic, Asn Tyr, Asn, Arg, Gln, Lys(Ac), His; Dap(Ac), Dab(Ac)or Asp;

X16 is any amino acid;X17 is absent;

X18 is D-Lys;

X19 is any amino acid or absent; andX20 is any amino acid or absent.

In particular embodiments of Is: X10 is Tyr, 1-Nal or 2-Nal; X11 is Trpor 1-Nal; X12 is Arg, Lys, His, hArg, Cit, Orn, 1-Nal, D-Ala, D-Leu,D-Phe, D-Asn, D-Asp, Agp, Leu, βhLeu, Aib, βhAla, βhVal, βhArg, hLeu orDap; X13 is Cha, Ogl, Aib, Leu, Val, Dab, Glu, Lys, βhLeu, βhAla, βhValor βGLu; X14 is Phe, Tic, Asn or Tyr; and X16 is AEA, Ala or βAla.

In particular embodiments, X5 is Glu, Arg, Ala, N-Me-Arg, N-Me-Ala,N-Me-Gln, Orn, N-Me-Asn, N-Me-Lys, Ser, Gln, Orn, Asn or Dap. Inparticular embodiments, X5 is Glu, Arg, Ala, N-Me-Arg, N-Me-Ala,N-Me-Gln, Orn, N-Me-Asn, N-Me-Lys, Ser, Asn or Dap.

In particular embodiments, X6 is Asp or Thr.

In particular embodiments, X8 is Gln or Val.

In particular embodiments, the peptide of Is is cyclized via a disulfidebond between X4 and X9.

In certain embodiments of the peptide inhibitor of Formula I, Xcomprises or consists of the sequence of Formula It:

X1-X2-X3-C-X5-X6-W-X8-C-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (It)

whereinX1 is any amino acid or absent;X2 is any amino acid or absent;X3 is any amino acid or absent;X5 is any amino acid;X6 is any amino acid;X8 is any amino acid;X10 is Tyr, 1-Nal, 2-Nal, Phe[4-(2-aminoethoxy)], Phe(4-CONH₂),Phe(4-OMe);

X11 is Trp, 1-Nal, 2-Nal, Bip, Phe(3,4-OMe₂) 5-Hydroxy-Trp;

X12 is Arg, His, 3-Pal, Leu, Thr, Gln, Asn, Glu, Ile, Phe, Ser, Lys,hLeu, α-MeLeu, D-Leu, D-Asn, h-Leu, 4-amino-4-carboxy-tetrahydropyran,Achc Acpc, Acbc, Acvc, Agp, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac),α-Me-Leu, α-MeOrn, α-MeSer or α-MeVal;

X13 is Thr, Glu, Tyr, Lys, Gln, Asn, Lys, Lys (Ac), Asp, Arg, Ala, Ser,Leu; X14 is Phe, Tyr, Asn, Gly, Ser, Met, Arg, His, Lys, Leu or Gln; X15is Gly, Ser, Arg, Leu, Asp, Ala, β-Ala, Glu, Arg or Asn;

X16 is absent or any amino acid;X17 is absent or any amino acid;X18 is any amino acid or absent;X19 is any amino acid or absent; andX20 is any amino acid or absent.

In certain embodiments of It: X10 is Tyr, 1-Nal or 2-Nal; X11 is Trp,1-Nal, 2-Nal or Bip; X12 is Arg, His, 3-Pal, Leu, Thr, Gln, Asn, Glu,Ile, Phe, Ser, Lys, hLeu, α-MeLeu, D-Leu, D-Asn, or h-Leu; X13 is Thr,Glu, Tyr, Lys, Gln, Asn, Lys, Asp, Arg, Ala, Ser, Leu; X15 is Gly, Ser,Arg, Leu, Asp or Ala; X16 is absent or Asn, Glu, Phe, Ala, Gly, Pro,Asp, Gln, Ser, Thr, D-Glu or Lys; and X17 is absent or Pro, Arg, Glu,Asp, Ser, Gly or Gln.

In particular embodiments, X5 is Ser, Asp, Asn, Gln, Ala, Met, Arg, Hisor Gly. In particular embodiments, X5 is Ser, Asp, Gln, Ala, Met, Arg,His or Gly.

In particular embodiments, X6 is any Asp, Ser or Thr.

In particular embodiments, X8 is Gln, Glu or Thr.

In particular embodiments, the peptide of It is cyclized via a disulfidebond between X4 and X9.

Any of the peptide inhibitors of the present invention (e.g., any ofthose of Formula I (e.g., Ix, Ia-It) may be further defined, e.g., asdescribed below. It is understood that each of the further definingfeatures described herein may be applied to any peptide inhibitors wherethe amino acids designated at particular positions allow the presence ofthe further defining feature.

In certain embodiments, the peptide inhibitor is cyclized by adisulphide bridge.

In certain embodiments, X10 is Tyr, Phe[4-(2-aminoethoxy)], Phe(4-CONH₂)or Phe(4-OMe). In certain embodiments, X10 is Tyr.

In certain embodiments, X11 is 2-Nal, Trp, or 5-Hydroxy-Trp. In certainembodiments, X11 is Trp.

In certain embodiments, X10 is Tyr or Phe[4-(2-aminoethoxy)], and X11 isTrp or 2-Nal. In certain embodiments, X10 is Tyr and X11 is Trp.

In particular embodiments, X4 and X9 are both Cys.

In particular embodiments, X4 is Cys, Pen, hCys, or absent.

In particular embodiments, X7 and X11 are not both W.

In particular embodiments, X7 and X11 are both W.

In particular embodiments, X7 and X11 are both W, X10 is Y, and X4 andX9 are both Cys.

In particular embodiments, X15 is Gly, Asn, β-ala or Ser. In particularembodiments, X15 is Gly or Ser.

In particular embodiments, X16 is AEA or AEP.

In particular embodiments, X10 is Tyr, Phe or Phe[4-(2-aminoethoxy). Inparticular embodiments, X10 is Tyr or Phe.

In particular embodiments, X11 is Trp or 2-Nal. In particularembodiments, X11 is Trp.

In particular embodiments, X1, X2 and X3 are absent.

In particular embodiments, X18, X19 and X20 are absent.

In particular embodiments, X1, X2, X3, X18, X19 and X20 are absent.

In particular embodiments, one or more of X1, X2 or X3 are present.

In particular embodiments of any of Ix, Ia-Ir, one of X1, X2 and X3 ispresent and the other two are absent. In one embodiment, the X1, X2 orX3 present is Ala.

In certain embodiments, X3 is present. In particular embodiments, X3 isGlu, (D)Glu, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, (D)Gln. Incertain embodiments, X3 is (D)Arg or (D)Phe. In particular embodiments,X1 and X2 are absent and X3 is present.

In particular embodiments, two of X1, X2 and X3 are present and theother one is absent. In certain embodiments, the two present consist ofSG, NK, DA, PE, QV or DR.

In particular embodiments, X1, X2 and X3 are present. In certainembodiments, X1, X2 and X3 consist of ADQ, KEN, VQE, GEE, DGF, NAD, ERN,RVG, KAN, or YED.

In certain embodiments, the peptide comprises an AEP residue. Inparticular embodiments, any of X15, X16, X17, X18, X19 or X20 is AEP.

In certain embodiments of any of the peptide inhibitors or peptidemonomer subunits, X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Lys(Ac),βhAla, or Aib. In certain embodiments of any of the peptide inhibitorsor peptide monomer subunits, X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys,βhAla, or Aib. In certain embodiments, X14 is Phe, Asn, Tyr, or βhPhe.In certain embodiments, X14 is Phe, Tyr, or βhPhe. In certainembodiments, X15 is Gly, Asn Ser, Thr, Gln, Ala, or Sarc. In certainembodiments, X15 is Gly, Ser, Thr, Gln, Ala, or Sarc. In certainembodiments, X12 is alpha amino acid, e.g.,4-amino-4-carboxy-tetrahydropyran, Achc Acpc, Acbc, Acvc, Aib,α-DiethylGly, α-MeLys, α-MeLys(Ac), α-Me-Leu, α-MeOrn, α-MeSer, orα-MeVal.

In certain embodiments, X13 is present.

In certain embodiments, X13 and 14 are present.

In certain embodiments, X13, X14 and X15 are present.

In particular embodiments of any one of Ia-It, one or more of X16-X20are present. In particular embodiments, two or more or three or more ofX16-X20 are present. In particular embodiments, X18 is [(D)Lys]. Inparticular embodiments, X17 is absent, and X18 is [(D)Lys]. In certainembodiments wherein X4 and X9 are optionally Cys, X4 and X9 are Cys, X7is Trp, and X18 is [(D)Lys]. In particular embodiments wherein X4 and X9are optionally Cys, X4 and X9 are Cys, X7 is Trp, X10 is Tyr orPhe[4-(2-aminoethoxy)], and X18 is [(D)Lys]. In particular embodimentswherein X4 and X9 are optionally Cys, X4 and X9 are Cys, X7 is Trp, X10is Tyr, and X18 is [(D)Lys]. In particular embodiments wherein X4 and X9are optionally Cys, X4 and X9 are Cys, X7 is Trp, X1, X2 and X3 areabsent, X17 is absent, X18 is [(D)Lys], and X19 and X20 are absent. Inparticular embodiments of Ir, X4 and X9 are Cys, X7 and X11 are Trp, X10is Tyr, and X18 is [(D)Lys. In certain embodiments, X1, X2, and X3 areabsent; and in certain embodiments, X17 is absent.

In certain embodiments, any of the peptide inhibitors (or monomersubunits) described herein is cyclized. In particular embodiments, thepeptide inhibitor is cyclized via a bond between two or more internalamino acids of the peptide inhibitor. In particular embodiments,cyclized peptide inhibitors are not cyclized via a bond between theN-terminal and C-terminal amino acids of the peptide inhibitor. Incertain embodiments, one of the amino acid residues participating in theintramolecular bond cyclizing the peptide in the amino terminal aminoacid residue. In certain embodiments, any of the peptide inhibitors incyclized via a peptide bond between its N-terminal amino acid and itsC-terminal amino acid.

In certain embodiments of any of the peptide inhibitors, or one or bothmonomer subunits thereof, the peptide inhibitor (or one or both monomersubunit thereof) is cyclized via an intramolecular bond between X4 andX9 or by a triazole ring. In particular embodiments, the intramolecularbond is any disulfide bond, a thioether bond, a lactam bond, a triazole,a selenoether bond, a diselendide bond, or an olefin bond.

In one embodiment, X4 and X9 of the peptide inhibitor (or one or bothmonomer subunits thereof) are Cys, Pen, hCys, D-Pen, D-Cys or D-hCys,and the intramolecular bond is a disulfide bond. In certain embodiments,both X4 and X9 are Cys, or both X4 and X9 are Pen, and theintramolecular bond is a disulfide bond.

In one embodiment, X4 and X9 of the peptide inhibitor (or one or bothmonomer subunits thereof) are Glu, Asp, Lys, Orn, Dap, Dab, D-Dap,D-Dab, D-Asp, D-Glu or D-Lys, and the intramolecular bond is a lactambond.

In one embodiment, X4 is Abu, 2-chloromethylbenzoic acid,mercapto-propanoic acid, mercapto-butyric acid, 2-chloro-acetic acid,3-choro-propanoic acid, 4-chloro-butyric acid, or 3-chloro-isobutyricacid; X9 is Abu, Cys, Pen, hCys, D-Pen, D-Cys or D-hCys; and theintramolecular bond is a thioether bond. In certain embodiments, X4 isAbu and X9 is Pen, and the intramolecular bond is a thioether bond. Inparticular embodiments, X4 is a 2-methylbenzoyl moiety capable offorming a thioether bond with X9, and X9 is selected from Cys, N-Me-Cys,D-Cys, hCys, Pen, and D-Pen. In particular embodiments, X4 is Abu and X9is Cys, and the intramolecular bond is a thioether bond. In particularinstances, a peptide monomer, dimer, or subunit thereof of any of theFormulas and peptides described herein, X4 is selected from the groupconsisting of modified Ser, modified hSer (e.g., Homo-Ser-C1), asuitable isostere, and corresponding D-amino acids. In other instances,X4 is an aliphatic acid having from one to four carbons and forming athioether bond with X9. In some instances, X4 is a five- or six-memberedalicyclic acid having a modified 2-methyl group that forms a thioetherbond with X9. In some embodiments, X4 is a 2-methylbenzoyl moiety. Incertain embodiments, X4 is selected from Cys, hCys, Pen, and a2-methylbenzoyl moiety. In certain embodiments, X4 is selected from thegroup consisting of a modified Ser, a modified hSer, a suitableisostere, and corresponding D-amino acids. In one embodiment, X4 is ahSerCl (before the thioether bond is formed with X9 whereby the Cl isremoved) or a hSer precursor (e.g., homoSer(O-TBDMS). In otherinstances, X4 is an aliphatic acid having from one to four carbons andforming a thioether bond with X9. In some instances, X4 is a five- orsix-membered alicyclic acid having a modified 2-methyl group that formsa thioether bond with X9. In some instances, X4 is a 2-methylbenzoylmoiety. In certain embodiments wherein X4 is not an amino acid but is achemical moiety that binds to X9, X1, X2, and X3 are absent, and X4 isconjugated to or bound to X5. In some embodiments, the amino aciddirectly carboxyl to X9 is an aromatic amino acid. In certainembodiments, X4 is an amino acid, while in other embodiments, X4 isanother chemical moiety capable of binding to X9, e.g., to form athioether bond. In particular embodiments, X4 is another chemical moietyselected from any of the non-amino acid moieties described herein forX4. In particular embodiments wherein X4 is another chemical moiety, X1,X2 and X3 are absent, and the another chemical moiety is bound to orconjugated to X5. In certain embodiments, X4 is defined as a chemicalmoiety including a group such as a chloride, e.g., in2-chloromethylbenzoic acid, 2-chloro-acetic acid, 3-choropropanoic acid,4-chlorobutyric acid, 3-chloroisobutyric acid. However, the skilledartisan will appreciate that once the peptide has undergone ring closingcyclization to form a thioether bond between X4 and X9, the chloridegroup is no longer present. The description of chemical moieties at X4that include a reactant group such as chloride thus means both the groupwith the chloride and also the group without the chloride, i.e., afterformation of the bond with X9. The present invention also includespeptides comprising the same structure as shown in any of the otherformulas or tables described herein, but where the thioether bond is inthe reverse orientation. In such embodiments of the invention, it maygenerally be considered that the amino acid residues or other chemicalmoieties shown at X4 are instead present at X9, and the amino acidresidues shown at X9 are instead present at X4, i.e., the amino acidresidue comprising the sulfur of the resulting thioether bond is locatedat X4 instead of X9, and the amino acid residue or other moiety having acarbon side chain capable of forming a thioether bond with X4 is locatedat X9. In this reverse orientation, however, the amino acid or chemicalmoiety at position X9 is one that comprises a free amine. For example,in particular embodiments, the amino acid at X9 is a protectedhomoserine, such as, e.g., homoserine (OTBDMS). Thus, in particularreverse orientation embodiments of peptide inhibitors of any of theformulas described herein, X9 is an amino acid residue having a sidechain with one or two carbons, and forming a thioether bond with X4, andX4 is selected from the group consisting of Cys, N-Me-Cys, D-Cys, HCys,Pen, and D-Pen. Specific examples of amino acid residues and otherchemical moieties present at corresponding positions of other formulasand tables are described herein.

One of skill in the art will appreciate that certain amino acids andother chemical moieties are modified when bound to another molecule. Forexample, an amino acid side chain may be modified when it forms anintramolecular bridge with another amino acid side chain, e.g., one ormore hydrogen may be removed or replaced by the bond. In addition, whenhSer-Cl binds to an amino acid such as Cys or Pen via a thioether bond,the Cl moiety is released. Accordingly, as used herein, reference to anamino acid or modified amino acid, such as hSer-Cl, present in a peptidedimer of the present invention (e.g., at position X4 or position X9) ismeant to include the form of such amino acid or modified amino acidpresent in the peptide both before and after forming the intramolecularbond.

In certain embodiments, the peptide inhibitor of the peptide inhibitor(or one or both monomer subunits thereof) is cyclized through a triazolering. In certain embodiments, the peptide inhibitor of the peptideinhibitor (or one or both monomer subunits thereof) is linear or notcyclized. In certain embodiments of any of the peptide inhibitorsdescribed herein, including both monomer peptide inhibitors and dimerpeptide inhibitors, one (or both) peptide monomer subunits comprise orconsist of a cyclized peptide having a structure or sequence set forthin any of Ix, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im, In,Io, Ip, Iq, Iq′, Ir, Is or It, IIa-IId, IIIa-IIIe, Iva, or IVb.

In certain embodiments of any of the peptide inhibitors or monomersubunits, X7 and X11 are both W.

In certain embodiments of any of the peptide inhibitors or monomersubunits, X7 and X11 are not both W. In particular embodiments, X7 is Wand X11 is not W.

In certain embodiments of any of the peptide inhibitors or monomersubunits, X4 and X9 are amino acid residues capable of forming anintramolecular bond between each other that is a thioether bond, alactam bond, a triazole, a selenoether, a diselenide bond, or an olefinbond.

In certain embodiments, X7 and X11 are both W, X10 is Y,Phe[4-(2-aminoethoxy) or Phe(CONH₂), and X4 and X9 are amino acidresidues capable of forming an intramolecular bond between each otherthat is a thioether bond, a lactam bond, a triazole, a selenoether, adiselenide bond, or an olefin bond. In certain embodiments, X7 and X11are both W, X10 is Y, and X4 and X9 are amino acid residues capable offorming an intramolecular bond between each other that is a thioetherbond, a lactam bond, a triazole, a selenoether, a diselenide bond, or anolefin bond.

In certain embodiments, X7 and X11 are both W, X10 is Y, and X4 and X9are both C.

In certain embodiments, X4 and X9 are each Cys, Pen, hCys, D-Pen, D-Cysor D-hCys, and the intramolecular bond is a disulfide bond.

In certain embodiments, X4 and X9 are each Glu, Asp, Lys, Orn, Dap, Dab,D-Dap, D-Dab, D-Asp, D-Glu or D-Lys, and the intramolecular bond is alactam bond.

In certain embodiments, X4 and X9 are each β-azido-Ala-OH orpropargylglycine, and the peptide inhibitor (or monomer subunit) iscyclized through a triazole ring.

In certain embodiments, X4 and X9 are each 2-allylglycine,2-(3′-butenyl)glycine, 2-(4′-pentenyl)glycine, or 2-(5′-hexenyl)glycinemand the peptide inhibitor (or monomer subunit) is cyclized via ringclosing methasis to give the corresponding olefin/“stapled peptide.”

In certain embodiments, X4 is 2-chloromethylbenzoic acid,mercapto-propanoic acid, mercapto-butyric acid, 2-chloro-acetic acid,3-choro-propanoic acid, 4-chloro-butyric acid, 3-chloro-isobutyric acid,or hSer(Cl); X9 is hSer(Cl), Cys, Pen, hCys, D-Pen, D-Cys or D-hCys; andthe intramolecular bond is a thioether bond. In certain embodiments, X4is 2-chloromethylbenzoic acid or hSer(Cl); X9 is Cys or Pen, and theintramolecular bond is a thioether bond. In certain embodiments, X4 isAbu, and X9 is Cys or Pen.

In certain embodiments, X4 is 2-chloromethylbenzoic acid,2-chloro-acetic acid, 3-choro-propanoic acid, 4-chloro-butyric acid,3-chloro-isobutyric acid, Abu or Sec; X9 is Abu or Sec; and theintramolecular bond is a selenoether bond.

In certain embodiments, the intramolecular bond between X4 and X9 is adiselenide bond.

In certain embodiments of any of the peptide inhibitors described hereinthat contain two amino acid residues, e.g., cysteine residues, joined byan intramolecular bond, e.g., disulphide bond, the two amino acidresidues participating in the intramolecular bond are not both locatedat either the N-terminal or C-terminal position of the peptideinhibitor. In certain embodiments, neither of the two amino acidresidues, e.g., cysteines, participating in the intramolecular bond islocated at the N-terminal or C-terminal position of the peptideinhibitor. In other words, in certain embodiments, at least one, orboth, of the two amino acid residues, e.g., cysteines, participating inthe intramolecular bond are internal amino acid residues of the peptideinhibitor. In certain embodiments, neither of the two amino acidresidues, e.g., cysteines, participating in the intramolecular bond islocated at the C-terminal position of the peptide inhibitor. At certainembodiment, the two amino acid residues participating in theintramolecular bond are Cys, Pen, hCys, D-Pen, D-Cys or D-hCys residues.In certain embodiments, the two amino acid residues participating in theintramolecular bond are located at X4 and X9. In one embodiment, thereis a disulfide bond between the amino acid residues, e.g., cysteines orPen residues, at X4 and X9.

In particular embodiments of any of the peptide inhibitors describedherein, one or both peptide monomer subunits present in the peptideinhibitor, whether it is a monomer or a dimer, is cyclic or cyclized,e.g., by an intramolecular bond, such as a disulfide bond, between twocysteine residues present in the peptide monomer or peptide monomersubunit. In certain embodiments, a peptide inhibitor comprises two ormore cysteine residues. In some embodiments, the peptide inhibitor iscyclized via an intramolecular disulfide bond between the two cysteineresidues. In particular embodiments of peptide inhibitors having any ofthe Formulas described herein, the two cysteines occur at positions X4and X9. In other embodiments, one or both peptide monomer subunits inthe peptide inhibitor is cyclized via a disulfide bond between two Penresidues, e.g., at positions X4 and X9.

In some embodiments, a peptide inhibitor has a structure of any of theFormulas described herein (e.g., Formula I and Formula III) andcomprises a disulfide bond, e.g., an intramolecular disulfide bond.Illustrative examples of such peptide inhibitors are shown in Tables3A-3H and 4A, 4B, 9, 11 or 15. Such disulfide bonded peptides may have aparticular advantage in that the disulfide bonds enhance structuralstability and can improve biological activity of many bioactivepeptides. However, in certain situations, these bonds are labile toreducing agents. One of skill in the art will appreciate that disulfideis amenable to simple isosteric replacement. Illustrative examples ofsuch replacements include, but are not limited to, thioethers,dithioethers, selenoethers, diselenides, triazoles, lacatams, alkane andalkene groups. Accordingly, in certain embodiments of any of the peptideinhibitors described herein, one, two or more cysteine residues aresubstituted, e.g., with a thioether, dithioether, selenoether,diselenide, triazoles, lacatam, alkane or alkene group, including butnot limited to any of those shown below or described herein. Inparticular embodiments, two of these substituted groups form a bond(e.g., an intramolecular bond), thus cyclizing the peptide inhibitor orone or both monomer subunits thereof.

In certain embodiments, a peptide inhibitor of the present inventioncomprises or consists of an amino acid sequence shown herein, e.g., inany one of Tables 3A-3H, 4A, 4B, 5A-5C, 6, 7, 8, 9, 10, 11, 12, 13, 14or 15. In certain embodiments, a peptide inhibitor of the presentinvention has a structure shown herein, e.g., in any one of Tables3A-3H, 4A, 4B, 5A-5C, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

In certain embodiments, the present invention includes a peptideinhibitor that comprises a core consensus sequence selected from one ofthe following (shown in N-terminal to C-terminal direction):

-   -   X₁X₂X₂WX₂X₁X₂W;    -   X₁X₂X₂WX₂X₁X₂ (1-Nal);    -   X₁X₂X₂WX₂X₁X₂ (2-Nal);    -   X₁X₂X₂WX₂X₁YW;    -   X₁X₂X₂WX₂X₁Y(1-Nal);    -   X₁X₂X₂WX₂X₁Y(2-Nal);    -   X₁X₂X₂WX₂X₁X₂X₂;    -   X₁X₂X₂WX₂X₁X₂X₂X₂X₂X₂-[(D)Lys];    -   X₁X₂X₂WX₂X₁X₃X₂;    -   X₁X₂X₂WX₂X₁X₃(1-Nal); and    -   X₁X₂X₂WX₂X₁X₃(2-Nal).

wherein W is tryptophan, Y is tyrosine, each the two X1 residues areamino acids or other chemical moieties capable of forming anintramolecular bond with each other; each X2 is independently selectedfrom all amino acids, which include, e.g., natural amino acids, L-aminoacids, D-amino acids, non-natural amino acids, and unnatural aminoacids; and X3 is any amino acid. In particular embodiments, X3 is Phe, aPhe analog (e.g., Phe[4-(2-aminoethoxy)] or Phe(4-CONH₂)), Tyr, or a Tyranalog (e.g., Tyr(Me)). In particular embodiments, each X1 is selectedfrom Cys, Pen and Abu. In particular embodiments, each X1 is Cys. Incertain embodiments, each X1 is Pen. In certain embodiments, one X1 isCys and the other X1 is Abu. In particular embodiments, the N-terminalX1 is Abu and the C-terminal X1 is Cys. In particular embodiments, theN-terminal X1 is Cys and the C-terminal X1 is Abu. In particularembodiments, the residues between the two X1 residues are Gln, Thr, Trpand Gln. In particular embodiments, each X1 is selected from Cys, Penand Abu; and X3 is Phe, a Phe analog (e.g., Phe[4-(2-aminoethoxy)] orPhe(4-carbomide)), Tyr, or a Tyr analog (e.g., Tyr(Me)). In particularembodiments, X3 is a Phe analog.

In certain embodiments, peptide inhibitors of the present inventioncomprises any of the following consensus sequences, wherein X1, X2, X3,X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14 and X15 are defined asshown in any of the various Formula or peptide inhibitors describedherein:

X1-X2-X3-Pen-X5-X6-W-X8-Pen-X10-X11-X12-X13-X14-X15; Pen-X5-X6-W-Q-Pen;Pen-X5-X6-W-X8-Pen; Pen-X5-X6-W-X8-Pen-[Phe(4-CONH2)];

Pen-X5-X6-W-X8-Pen-[Phe[4-(2-aminoethoxy)]];

X1-X2-X3-Abu-X5-X6-W-X8-C-X9-X10-X11-X12-X13-X14-X15; Abu-X5-X6-W-Q-C;Abu-X5-X6-W-X8-C; Abu-X5-X6-W-X8-C-[Phe(4-CONH2)]; or

Abu-X5-X6-W-X8-C-[Phe[4-(2-aminoethoxy)]].

In certain embodiments of any of the peptide inhibitors or monomersubunits, X7 and X11 are both W. In certain embodiments of any of thepeptide inhibitors, X7 and X11 are both W, and X10 is Y. In certainembodiments, X7 and X11 are both W and X10 is Phe[4-(2-aminoethoxy)] orPhe(4-OMe).

In certain embodiments of any of the peptide inhibitors or monomersubunits, X7 and X11 are not both W.

In certain embodiments of peptide inhibitors of Formula I, X4 and X9 areeach Pen, and the intramolecular bond is a disulfide bond.

In certain embodiments, a peptide inhibitor of the present inventioncomprises or consists of an amino acid sequence shown in any one of thetables or the accompanying figures herein. In certain embodiments, apeptide inhibitor of the present invention has a structure shown in anyone of Tables 3A-3H, 4A, 4B, 5A-5C, or 6-14.

In certain embodiments of any of the peptide inhibitors described hereinthat contain two amino acid residues, e.g., Pen residues, joined by anintramolecular bond, e.g., disulphide bond, one or both of the two aminoacid residues participating in the intramolecular bond are not locatedat either the N-terminal or C-terminal position of the peptideinhibitor. In certain embodiments, neither of the two amino acidresidues, e.g., Pen, participating in the intramolecular bond is locatedat the N-terminal or C-terminal position of the peptide inhibitor. Inother words, in certain embodiments, at least one, or both, of the twoamino acid residues, e.g., Pens, participating in the intramolecularbond are internal amino acid residues of the peptide inhibitor. Incertain embodiments, neither of the two amino acid residues, e.g., Pens,participating in the intramolecular bond is located at the C-terminalposition of the peptide inhibitor.

In some embodiments, wherein a peptide of the invention is conjugated toan acidic compound such as, e.g., isovaleric acid, isobutyric acid,valeric acid, and the like, the presence of such a conjugation isreferenced in the acid form. So, for example, but not to be limited inany way, instead of indicating a conjugation of isovaleric acid to apeptide by referencing isovaleroyl (e.g., isovaleroyl-[Pen]-QTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ (SEQ ID NO: 262)in some embodiments, the present application references such aconjugation as isovaleric acid-[Pen]-QTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ (SEQ ID NO: 263).

The present invention further includes peptide inhibitors thatselectively bind to an epitope or binding domain present within aminoacid residues 230-349 of the human IL23R protein. In particularembodiments, the peptide inhibitor binds human IL23R and not mouseIL-23R. In certain embodiments, the peptide inhibitor also binds to ratIL-23R.

In certain embodiments of peptide inhibitors of Formula I, X4 is Abu; X9is Cys, Pen, homocys, and the intramolecular bond is a thioether bond.

In certain embodiments of Formula I, X4 is Cys, Pen, hCys, D-Pen, D-Cysor D-hCys; X9 is Abu; and the intramolecular bond is a thioether bond.

Illustrative Peptide Inhibitors Comprising Pen-Pen Disulfide Bonds

In certain embodiments, the present invention includes a peptideinhibitor of an interleukin-23 receptor, wherein the peptide inhibitorhas the structure of Formula II:

R¹—X—R²  (II)

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ isa bond, hydrogen, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12 aryl, a C1-C6alkyl, a C1-C20 alkanoyl, an alkylsulphonate, an acid, γ-Glu or pGlu,appended to the N-terminus, and including PEGylated versions (e.g., 200Da to 60,000 Da), alone or as a spacer of any of the foregoing;

R² is a bond, OH or NH₂; and

X is an amino acid sequence of 8 to 20 amino acids or 8 to 35 aminoacids.

In particular embodiments of peptide inhibitor of Formula II, Xcomprises or consists of the sequence of Formula IIa:

X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (IIa)

whereinX1 is absent or any amino acid;X2 is absent or any amino acid;X3 is absent or any amino acid;X4 is Pen, Cys or homo-Cys;X5 is any amino acid;X6 is any amino acid;X7 is Trp, Bip, Gln, His, Glu(Bzl), 4-Phenylbenzylalanine, Tic,Phe[4-(2-aminoethoxy)], Phe(3,4-Cl₂), Phe(4-OMe), 5-Hydroxy-Trp,6-Chloro-Trp, N-MeTrp, α-Me-Trp, 1,2,3,4-tetrahydro-norharman,Phe(4-CO₂H), Phe(4-CONH₂), Phe(3,4-Dimethoxy), Phe(4-CF₃), Phe(4-tBu),ββ-diPheAla, Glu, Gly, Ile, Asn, Pro, Arg, Thr or Octgly, or acorresponding α-methyl amino acid form of any of the foregoing;X8 is any amino acid;X9 is Pen, Cys or hCys;X10 is 1-Nal, 2-Nal, Aic, Bip, (D)Cys, Cha, DMT, (D)Tyr, Glu, Phe, His,Trp, Thr, Tic, Tyr, 4-pyridylAla, Octgly, a Phe analog or a Tyr analog(optionally, Phe(3,4-F₂), Phe(3,4-Cl₂), F(3-Me), Phe[4-(2-aminoethoxy)],Phe[4-(2-(acetyl-aminoethoxy)], Phe(4-Br), Phe(4-CONH₂), Phe(4-C1),Phe(4-CN), Phe(4-guanidino), Phe(4-Me), Phe(4-NH₂), Phe(4-N₃),Phe(4-OMe), or Phe(4-OBzl)), or a corresponding α-methyl amino acid formof any of the foregoing;X11 is 2-Nal, 1-Nal, 2,4-dimethylPhe, Bip, Phe(3,4-Cl₂), Phe (3,4-F₂),Phe(4-CO₂H), βhPhe(4-F), α-Me-Trp, 4-phenylcyclohexyl, Phe(4-CF₃),α-MePhe, βhPhe, βhTyr, βhTrp, Nva(5-phenyl), Phe, His, hPhe, Tic, Tqa,Trp, Tyr, Phe(4-OMe), Phe(4-Me), Trp(2,5,7-tri-tert-Butyl),Phe(4-Oallyl), Tyr(3-tBu), Phe(4-tBu), Phe(4-guanidino, Phe(4-OBzl),Octgly, Glu(Bzl), 4-Phenylbenzylalanine, Phe[4-(2-aminoethoxy)],5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, 1,2,3,4-tetrahydro-norharman,Phe(4-CONH₂), Phe(3,4-OMe₂) Phe(2,3-Cl₂), Phe(2,3-F₂), Phe(4-F),4-phenylcyclohexylalanine or Bip, or a corresponding α-methyl amino acidform of any of the foregoing;X12 is α-MeLys, α-MeOrn, α-MeLeu, α-MeVal,4-amino-4-carboxy-tetrahydropyran, Achc Acpc, Acbc, Acvc, MeLeu, Aib,(D)Ala, (D)Asn, (D)Leu, (D)Asp, (D)Phe, (D)Thr, 3-Pal, Aib, β-Ala,βhGlu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Dab, Dap,α-DiethylGly, Glu, Phe, hLeu, hArg, hLeu, Ile, Lys, Leu, Asn, N-MeLeu,N-MeArg, Ogl, Orn, Pro, Gln, Arg, Ser, Thr or Tle, or a correspondingα-methyl amino acid form of any of the foregoing;X13 is Lys(Ac), (D)Asn, (D)Leu, (D)Thr, (D)Phe, Ala, Aib, α-MeLeu,β-Ala, βhGlu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Lys, Arg,Orn, Dab, Dap, α-DiethylGly, Glu, Phe, hLeu, Lys, Leu, Asn, Ogl, Pro,Gln, Asp, Arg, Ser, spiro-pip, Thr, Tba, Tlc, Val or Tyr, or acorresponding α-methyl amino acid form of any of the foregoing;X14 is Asn, Glu, Phe, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser,Thr, Tic or Tyr, Lys(Ac), Orn or a corresponding α-methyl amino acidform of any of the foregoing;X15 is Gly, (D)Ala, (D)Asn, (D)Asp, Asn, (D)Leu, (D)Phe, (D)Thr, Ala,AEA, Asp, Glu, Phe, Gly, Lys, Leu, Pro, Gln, Arg or Ser, β-Ala, Arg or acorresponding α-methyl amino acid form of any of the foregoing;X16 is absent, Gly, Ala, Asp, Ser, Pro, Asn or Thr, or a correspondingα-methyl amino acid form of any of the foregoing;X17 is absent, Glu, Ser, Gly or Gln, or a corresponding α-methyl aminoacid form of any of the foregoing;X18 is absent or any amino acid;X19 is absent or any amino acid; andX20 is absent or any amino acid.

In certain embodiments of Ha: X10 is 1-Nal, 2-Nal, Aic, Bip, (D)Cys,Cha, DMT, (D)Tyr, Glu, Phe, His, Trp, Thr, Tic, Tyr, 4-pyridylAla,Octgly, a Phe analog or a Tyr analog, or a corresponding α-methyl aminoacid form of any of the foregoing; X11 is 2-Nal, 1-Nal, 2,4-dimethylPhe,Bip, Phe(3,4-Cl₂), Phe (3,4-F₂), Phe(4-CO₂H), βhPhe(4-F), α-Me-Trp,4-phenylcyclohexyl, Phe(4-CF₃), α-MePhe, βhNal, βhPhe, βhTyr, βhTrp,Nva(5-phenyl), Phe, His, hPhe, Tic, Tqa, Trp, Tyr, Phe(4-OMe),Phe(4-Me), Trp(2,5,7-tri-tert-Butyl), Phe(4-Oallyl), Tyr(3-tBu),Phe(4-tBu), Phe(4-guanidino, Phe(4-OBzl), Octgly, Glu(Bzl),4-Phenylbenzylalanine, Phe[4-(2-aminoethoxy)], 5-Hydroxy-Trp,6-Chloro-Trp, N-MeTrp, 1,2,3,4-tetrahydro-norharman, Phe(4-CONH₂),Phe(3,4-Dimethoxy), Phe(2,3-Cl₂), Phe(2,3-F₂), Phe(4-F),4-phenylcyclohexylalanine or Bip, or a corresponding α-methyl amino acidform of any of the foregoing; X12 is α-MeLys, α-MeOrn, α-MeLeu, MeLeu,Aib, (D)Ala, (D)Asn, (D)Leu, (D)Asp, (D)Phe, (D)Thr, 3-Pal, Aib, β-Ala,βhGlu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Dab, Dap,α-DiethylGly, Glu, Phe, hLeu, hArg, hLeu, Ile, Lys, Leu, Asn, N-MeLeu,N-MeArg, Ogl, Orn, Pro, Gln, Arg, Ser, Thr or Tle, or a correspondingα-methyl amino acid form of any of the foregoing; X13 is Lys(Ac),(D)Asn, (D)Leu, (D)Thr, (D)Phe, Ala, Aib, α-MeLeu, β-Ala, βhGlu, βhAla,βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Lys, Arg, Orn, Dab, Dap,α-DiethylGly, Glu, Phe, hLeu, Lys, Leu, Asn, Ogl, Pro, Gln, Asp, Arg,Ser, spiro-pip, Thr, Tba, Tlc, Val or Tyr, or a corresponding α-methylamino acid form of any of the foregoing; X14 is Asn, Glu, Phe, Gly, His,Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic or Tyr, or acorresponding α-methyl amino acid form of any of the foregoing; and X15is Gly, (D)Ala, (D)Asn, (D)Asp, Asn, (D)Leu, (D)Phe, (D)Thr, Ala, AEA,Asp, Glu, Phe, Gly, Lys, Leu, Pro, Gln, Arg or Ser, or a correspondingα-methyl amino acid form of any of the foregoing.

In certain embodiments, X3 is present. In particular embodiments, X3 isGlu, (D)Glu, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, (D)Gln. Incertain embodiments, X3 is (D)Arg or (D)Phe. In particular embodiments,X1 and X2 are absent and X3 is present.

In certain embodiments, X5 is Gln, Ala, Cit, Asp, Dab, Dap, Cit Glu,Phe, Gly, His, hCys, Lys, Leu, Met, Asn, N-Me-Ala, N-Me-Asn, N-Me-Lys,α-Me-Lys, α-Me-Orn, N-Me-Gln, N-Me-Arg, α-MeSer, Orn, Pro, Arg, Ser,Thr, or Val. In certain embodiments, X5 is Gln, Ala, Cit, Asp, Dab, Dap,Glu, Phe, Gly, His, hCys, Lys, Leu, Met, Asn, N-Me-Ala, N-Me-Asn,N-Me-Lys, αMe-Lys, αMe-Orn, N-Me-Gln, N-Me-Arg, Orn, Pro, Arg, Ser, Thr,or Val. In certain embodiments, X5 is Gln or Asn.

In certain embodiments, X6 is Thr, Asp, Glu, Phe, Asn, Pro, Arg, or Ser.

In certain embodiments, X7 is Trp.

In certain embodiments, X8 is Gln, Glu, Phe, Lys, Asn, Pro, Arg, Val,Thr, or Trp.

In certain embodiments, X10 is a Tyr analog or a Phe analog. Inparticular embodiments, X10 is a Phe analog.

In certain embodiments wherein X10 is a Phe analog, X10 is selected fromhPhe, Phe(4-OMe), α-Me-Phe, hPhe(3,4-dimethoxy), Phe(4-CONH₂),Phe(4-phenoxy), Phe(4-guanadino), Phe(4-tBu), Phe(4-CN), Phe(4-Br),Phe(4-OBzl), Phe(4-NH₂), Phe(4-F), Phe(3,5 DiF), Phe(CH₂CO₂H),Phe(penta-F), Phe(3,4-Cl₂), Phe(4-CF₃), ββ-diPheAla, Phe(4-N₃) andPhe[4-(2-aminoethoxy)]. In particular embodiments, X10 is Phe(4-OMe) orPhe[4-(2-aminoethoxy)]. In particular embodiments, X10 is Phe(4-OMe),Phe(4-CONH₂) or Phe[4-(2-aminoethoxy)]. In certain embodiments where X10wherein X10 is a Phe analog, X10 is selected from hPhe, Phe(4-OMe),α-Me-Phe, hPhe(3,4-dimethoxy), Phe(4-CONH₂), Phe(4-phenoxy),Phe(4-guanadino), Phe(4-tBu), Phe(4-CN), Phe(4-Br), Phe(4-OBzl),Phe(4-NH₂), Phe(4-F), Phe(3,5 DiF), Phe(CH₂CO₂H), Phe(penta-F),Phe(3,4-Cl₂), Phe(4-CF₃), ββ-diPheAla, Phe(4-N₃) andPhe[4-(2-aminoethoxy)]. In particular embodiments, X10 is Phe(4-OMe).

In certain embodiments where X10 is a Tyr analog, X10 is selected fromhTyr, α-MeTyr, N-Me-Tyr, Tyr(3-tBu), Phe(4-CONH₂),Phe[4-(2-aminoethoxy)], and bhTyr. In certain embodiments where X10 is aTyr analog, X10 is selected from hTyr, α-MeTyr, N-Me-Tyr, Tyr(3-tBu),and bhTyr.

In certain embodiments, X10 is Tyr, Phe(4-OMe), Phe[4-(2-aminoethoxy)],Phe(4-CONH₂), or 2-Nal. In certain embodiments, X10 is Phe(4-OMe) orPhe[4-(2-aminoethoxy)]. In certain embodiments, X10 is not Tyr.

In certain embodiments, X11 is a Trp analog. In particular embodiments,X11 is 2-Nal or 1-Nal. In certain embodiments, X11 is 2-Nal.

In certain embodiments, X12 is Aib, α-MeLys or α-MeLeu.

In particular embodiments of a peptide inhibitor of Formula II, one orboth of X4 or X9 is Pen. In particular embodiments, both X4 and X9 arePen.

In certain embodiments, the peptide inhibitor of Formula II is cyclized.In particular embodiments, the peptide inhibitor of Formula II iscyclized via an intramolecular bond between X4 and X9. In particularembodiments, the intramolecular bond is a disulfide bond. In particularembodiments, X4 and X9 are both Pen.

In certain embodiments, the peptide inhibitor of Formula II is linear ornot cyclized. In particular embodiments of the linear peptide inhibitorof Formula I, X4 and/or X9 are any amino acid.

In particular embodiments of a peptide inhibitor of Formula II, one ormore, two or more, or all three of X1, X2, and X3 are absent. In certainembodiments, X1 is absent. In certain embodiments, X1 and X2 are absent.In certain embodiments, X1, X2 and X3 are absent.

In particular embodiments of a peptide inhibitor of Formula II, one ormore, two or more, three or more, four or more, or all of X16, X17, X18,X19 and X20 are absent. In particular embodiments of a peptide inhibitorof Formula I, one or more, two or more, three or more, or all of X17,X18, X19 and X20 are absent. In certain embodiments, one or more, two ormore, or all three of X17, X19 and X20 are absent. In certainembodiments, one or more of X1, X2 and X3 are absent; and one or more,two or more, three or more, or four of X17, X18, X19 and X20 are absent.

In particular embodiments of a peptide inhibitor of Formula II, X18 is(D)-Lys. In certain embodiments, X18 is (D)-Lys and X17 is absent.

In particular embodiments of a peptide inhibitor of Formula II, thepeptide inhibitor comprises one or more, two or more, three or more, orfour of the following features: X5 is Asn, Arg or Gln; X6 is Thr; X7 isTrp; and X8 is Gln. In particular embodiments of a peptide inhibitor ofFormula I, X4 is Pen; X5 is Gln, Asn or Arg; X6 is Thr; X7 is Trp,5-hydroxy-Trp, 6-chloro-Trp, N-MeTrp, alpha-Me-Trp, or1,2,3,4-tetrahydro-norharman; X8 is Gln; and X9 is Pen. In particularembodiments, X5 is Gln. In certain embodiments, X1, X2 and X3 areabsent. In particular embodiments, both X4 and X9 are Pen.

In particular embodiments of a peptide inhibitor of Formula II, thepeptide inhibitor comprises one or more, two or more, three or more,four or more, five or more, six or more, or seven of the followingfeatures: X10 is Tyr, a Phe analog, a Tyr analog or 2-Nal; X11 is Trp,5-hydroxy-Trp, 6-chloro-Trp, N-MeTrp, alpha-Me-Trp,1,2,3,4-tetrahydro-norharman, 2-Nal or 1-Nal; X12 is Aib, α-MeLys,α-MeOrn and α-MeLeu; X13 is Lys, Glu or Lys(Ac); X14 is Phe or Asn; X15is Gly, Ser or Ala; and X16 is absent or AEA. In certain embodiments,X10 is Tyr, Phe(4-OMe), Phe[4-(2-aminoethoxy)], Phe(CONH₂), or 2-Nal. Incertain embodiments, X11 is 2-Nal or 1-Nal. In certain embodiments, X10is not Tyr. In certain embodiments, X1, X2 and X3 are absent. Inparticular embodiments, both X4 and X9 are Pen.

In particular embodiments of a peptide inhibitor of Formula II, thepeptide inhibitor comprises one or more, two or more, three or more,four or more, five or more, six or more, seven or more, eight or more,nine or more, ten or more, or eleven of the following features: X5 isArg or Gln; X6 is Thr; X7 is Trp; X8 is Gln; X10 is a Phe analog; X11 isTrp, 2-Nal or 1-Nal; X12 is Aib, α-MeLys or α-MeOrn; X13 is Lys, Glu orLys(Ac); X14 is Asn; X15 is Gly, Ser or Ala; and X16 is absent or AEA.In certain embodiments, X10 is Phe(4-OMe) or Phe[4-(2-aminoethoxy)]. Incertain embodiments, X11 is 2-Nal or 1-Nal. In certain embodiments, X1,X2 and X3 are absent. In particular embodiments, both X4 and X9 are Pen.

In particular embodiments of a peptide inhibitor of Formula II, thepeptide is cyclized via X4 and X9; X4 and X9 are Pen; X5 is Gln; X6 isThr; X7 is Trp; X8 is Gln; X10 is Tyr, a Phe analog or 2-Nal; X11 isTrp, 2-Nal or 1-Nal; X12 is Arg, α-MeLys, α-MeOrn, or α-MeLeu; X13 isLys, Glu or Lys(Ac); X14 is Phe or Asn; X15 is Gly, Ser or Ala; and X16is absent. In certain embodiments, X10 is Tyr, Phe(4-OMe),Phe[4-(2-aminoethoxy)], Phe(4-OMe) or 2-Nal. In certain embodiments, X10is Phe(4-OMe). In certain embodiments, X10 is not Tyr. In certainembodiments, X11 is 2-Nal or 1-Nal. In certain embodiments, X1, X2 andX3 are absent.

In particular embodiments of a peptide inhibitor of Formula II, thepeptide is cyclized via X4 and X9; X4 and X9 are Pen; X5 is Gln; X6 isThr; X7 is Trp; X8 is Gln; X10 is Tyr, Phe(4-OMe) or 2-Nal; X11 is Trp,2-Nal or 1-Nal; X12 is Arg, α-MeLys or α-MeOrn; X13 is Lys, Glu orLys(Ac); X14 is Phe or Asn; X15 is Gly; and X16 is absent. In certainembodiments, X10 is Phe(4-OMe). In certain embodiments, X11 is 2-Nal or1-Nal. In certain embodiments, X1, X2 and X3 are absent.

In particular embodiments of a peptide inhibitor of Formula II, thepeptide is cyclized via X4 and X9; X4 and X9 are Pen; X5 is Gln; X6 isThr; X7 is Trp; X8 is Gln; X10 is Phe(4-OMe) or Phe[4-(2-aminoethoxy)];X11 is Trp, 2-Nal or 1-Nal; X12 is α-MeLys, α-MeOrn, or α-MeLeu; X13 isLys, Glu or Lys(Ac); X14 is Asn; X15 is Gly, Ser or Ala; and X16 isabsent. In certain embodiments, X10 is Phe(4-OMe). In certainembodiments, X11 is 2-Nal or 1-Nal. In certain embodiments, X1, X2 andX3 are absent.

In particular embodiments of a peptide inhibitor of Formula II, X10 isnot Tyr.

In certain embodiments, the present invention includes a peptide,optionally 8 to 35, 8 to 20, 8 to 16 or 8 to 12 amino acids in length,optionally cyclized, comprising or consisting of having a core sequenceof Formula IIb:

Pen-Xaa5-Xaa6-Trp-Xaa8-Pen-Xaa10-[(2-Nal)]  (IIb)

wherein Xaa5, Xaa6 and Xaa8 are any amino acid residue; and Xaa10 is aPhe analogue, wherein the peptide inhibits binding of IL-23 to IL-23R.In particular embodiments, X10 is a Phe analog selected from α-Me-Phe,Phe(4-OMe), Phe(4-OBzl), Phe(4-OMe), Phe(4-CONH₂), Phe(3,4-Cl₂),Phe(4-tBu), Phe(4-NH₂), Phe(4-Br), Phe(4-CN), Phe(4-CO₂H),Phe[4-(2-aminoethoxy)] or Phe(4-guanadino). In particular embodiments,Xaa10 is Phe(4-OMe) or Phe[4-(2-aminoethoxy)]. In one embodiment, Xaa10is Phe(4-OMe). In certain embodiments, the peptide is cyclized via anintramolecular bond between Pen at Xaa4 and Pen at Xaa9. In particularembodiments, the peptide is a peptide inhibitor of Formula II, andwherein in certain embodiments, X1, X2 and X3 are absent. In particularembodiments, the peptide inhibits the binding of IL-23 to IL-23R. Incertain embodiments, a peptide of Formula IIb further comprises an aminoacid bound to the N-terminal Pen residue. In particular embodiments, thebound amino acid is Glu, (D)Glu, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr,Leu, or (D)Gln. In certain embodiments, it is is (D)Arg or (D)Phe.

In certain embodiments, the present invention includes a peptide,optionally 8 to 35, 8 to 20, 8 to 16, or 8 to 12 amino acids in length,optionally cyclized, comprising or consisting of a core sequence ofFormula IIc:

Pen-Xaa5-Xaa6-Trp-Xaa8-Pen-Xaa10-[(2-Nal)]  (IIc)

wherein Xaa5, Xaa6 and Xaa8 are any amino acid residue; and Xaa10 isTyr, a Phe analog, α-Me-Tyr, α-Me-Trp or 2-Nal, wherein the peptideinhibits binding of IL-23 to IL-23R. In certain embodiments, X10 is Tyr,Phe(4-OMe), Phe[4-(2-aminoethoxy)], α-Me-Tyr, α-Me-Phe, α-Me-Trp or2-Nal. In certain embodiments, Xaa10 is Tyr, Phe(4-OMe), Phe(CONH₂),Phe[4-(2-aminoethoxy)] or 2-Nal. In certain embodiments, Xaa10 is Tyr,Phe(4-OMe), Phe[4-(2-aminoethoxy)] or 2-Nal. In particular embodiments,Xaa10 is Phe(4-OMe) or Phe[4-(2-aminoethoxy)]. In one embodiment, Xaa10is Phe[4-(2-aminoethoxy)] or Phe(CONH₂). In particular embodiments,Xaa10 is Phe(4-OMe) or Phe[4-(2-aminoethoxy)]. In one embodiment, Xaa10is Phe[4-(2-aminoethoxy)]. In certain embodiments, Xaa10 is not Tyr. Incertain embodiments, the peptide is cyclized via an intramolecular bondbetween Pen at Xaa4 and Pen at Xaa9. In particular embodiments, thepeptide is a peptide inhibitor of Formula II, and wherein in certainembodiments, X1, X2 and X3 are absent. In particular embodiments, thepeptide inhibits the binding of IL-23 to IL-23R. In certain embodiments,a peptide of Formula IIc further comprises an amino acid bound to theN-terminal Pen residue. In particular embodiments, the bound amino acidis Glu, (D)Glu, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, or (D)Gln. Incertain embodiments, it is is (D)Arg or (D)Phe.

In certain embodiments, the present invention includes a peptide,optionally 8 to 35, 8 to 20, 8 to 16 or 8 to 12 amino acids in length,optionally cyclized, comprising or consisting of a core sequence ofFormula IId:

Pen-Xaa5-Xaa6-Trp-Xaa8-Pen-Phe[4-(2-aminoethoxy)]-[2-Nal]  (IId)

wherein Xaa5, Xaa6 and Xaa8 are any amino acid residue. In certainembodiments, the peptide comprises a disulfide bond between Xaa4 andXaa9. In certain embodiments, the peptide is a peptide inhibitor ofFormula I, and wherein in certain embodiments, X1, X2 and X3 are absent.In particular embodiments, the peptide inhibits the binding of IL-23 toIL-23R. In certain embodiments, a peptide of Formula IId furthercomprises an amino acid bound to the N-terminal Pen residue. Inparticular embodiments, the bound amino acid is Glu, (D)Glu, Arg,(D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, or (D)Gln. In certain embodiments,it is is (D)Arg or (D)Phe.

In particular embodiments of a peptide inhibitor of Formula II, thepeptide inhibitor has a structure shown in any of Tables 4A, 4B, 8, 11or 15 or comprises an amino acid sequence set forth in Tables 4A, 4B, 8,11 or 15.

Illustrative Peptide Inhibitors Comprising Thioether Bonds

In certain embodiments, the present invention includes a peptideinhibitor of an interleukin-23 receptor, wherein the peptide inhibitorhas the structure of Formula III:

R¹—X—R²  (III)

or a pharmaceutically acceptable salt or solvate thereof,

wherein R¹ is a bond, hydrogen, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12aryl, a C1-C6 alkyl, a C1-C20 alkanoyl, an alkylsulphonate, an acid,γ-Glu or pGlu, appended to the N-terminus, and including PEGylatedversions (e.g., 200 Da to 60,000 Da), alone or as a spacer of any of theforegoing;

R² is a bond, OH or NH₂; and

X is an amino acid sequence of 8 to 20 amino acids or 8 to 35 aminoacids,

In particular embodiments of peptide inhibitors of Formula III, Xcomprises or consists of the sequence of Formula IIIa:

X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (IIIa)

whereinX1 is absent or any amino acid;X2 is absent or any amino acid;X3 is absent or any amino acid;

X4 is Abu, Pen, or Cys;

X5 is any amino acid;X6 is any amino acid;X7 is Trp, Bip, Gln, His, Glu(Bzl), 4-Phenylbenzylalanine, Tic,Phe[4-(2-aminoethoxy)], Phe(3,4-Cl₂), Phe(4-OMe), 5-Hydroxy-Trp,6-Chloro-Trp, N-MeTrp, α-MeTrp, 1,2,3,4-tetrahydro-norharman,Phe(4-CO₂H), Phe(4-CONH₂), Phe(3,4-(OCH₃)₂), Phe(4-CF₃), ββ-diPheAla,Phe(4-tBu), Glu, Gly, Ile, Asn, Pro, Arg, Thr or Octgly, or acorresponding α-methyl amino acid form of any of the foregoing;X8 is any amino acid;

X9 is Abu, Pen, or Cys;

X10 is 1-Nal, 2-Nal, Aic, Bip, (D)Cys, Cha, DMT, (D)Tyr, Glu, Phe, His,Trp, Thr, Tic, Tyr, 4-pyridylAla, Octgly a Phe analog or a Tyr analog(optionally, Phe(3,4-F₂), Phe(3,4-Cl₂), F(3-Me), Phe[4-(2-aminoethoxy)],Phe[4-(2-(acetyl-aminoethoxy)], Phe(4-Br), Phe(4-CONH₂), Phe(4-Cl),Phe(4-CN), Phe(4-guanidino), Phe(4-Me), Phe(4-NH₂), Phe(4-N₃),Phe(4-OMe), Phe(4-OBzl)), or a corresponding α-methyl amino acid form ofany of the foregoing;X11 is 2-Nal, 1-Nal, 2,4-dimethylPhe, Bip, 4-phenylcyclohexyl, Glu(Bzl),4-Phenylbenzylalanine, Tic, Phe[4-(2-aminoethoxy)], Phe(3,4-Cl₂),Phe(3,4-F₂), βhPhe(4-F), Phe(4-OMe), 5-Hydroxy-Trp, 6-Chloro-Trp,N-MeTrp, α-MeTrp, 1,2,3,4-tetrahydro-norharman, Phe(4-CO₂H),Phe(4-CONH₂), Phe(3,4-Dimethoxy), Phe(4-CF₃), Phe(2,3-Cl₂),Phe(3,4-Cl₂), Phe(2,3-F₂), Phe(4-F), 4-phenylcyclohexylalanine, α-MePhe,βhPhe, βhTyr, βhTrp, Bip, Nva(5-phenyl), Phe, His, hPhe, Tqa, Trp, Tyr,Phe(4-Me), Trp(2,5,7-tri-tertButyl), Phe(4-OAllyl), Tyr(3-tBu),Phe(4-tBu), Phe(4-guanidino), Phe(4-OBzl), or Octgly, or a correspondingα-methyl amino acid form of any of the foregoing;X12 is α-MeLys, α-MeOrn, α-MeLeu, MeLeu, Aib, (D)Ala, (D)Asn, (D)Leu,(D)Asp, (D)Phe, (D)Thr, 3-Pal, Aib, β-Ala, βhGlu, βhAla, βhLeu, βhVal,β-spiro-pip, Cha, Chg, Asp, Dab, Dap, α-DiethylGly, Glu, Phe, hLeu,hArg, hLeu, Ile, Lys, Leu, Asn, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln,Arg, Ser, Thr or Tle, amino-4-carboxy-tetrahydropyran, Achc Acpc, Acbc,Acvc, Aib, or a corresponding α-methyl amino acid form of any of theforegoing;X13 is Lys Lys(Ac), (D)Asn, (D)Leu, (D)Thr, (D)Phe, Ala, Aib, α-MeLeu,βAla, βhGlu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Arg, Orn,Dab, Dap, α-DiethylGly, Glu, Phe, hLeu, Lys, Leu, Asn, Ogl, Pro, Gln,Asp, Arg, Ser, spiro-pip, Thr, Tba, Tlc, Val or Tyr, or a correspondingα-methyl amino acid form of any of the foregoing;X14 is Asn, Glu, Phe, Gly, His, Lys, Lys (Ac), Leu, Met, Asn, Pro, Gln,Arg, Ser, Thr, Tic or Tyr, or a corresponding α-methyl amino acid formof any of the foregoing;X15 is Gly, (D)Ala, (D)Asn, (D)Asp, Asn, (D)Leu, (D)Phe, (D)Thr, Ala,AEA, Asp, Glu, Phe, Gly, Lys, Leu, Pro, Gln, Arg, β-Ala, or Ser, or acorresponding α-methyl amino acid form of any of the foregoing;X16 is absent, Gly, Ala, Asp, Ser, Pro, Asn or Thr, or a correspondingα-methyl amino acid form of any of the foregoing;X17 is absent, Glu, Ser, Gly or Gln, or a corresponding α-methyl aminoacid form of any of the foregoing;X18 is absent or any amino acid;X19 is absent or any amino acid; andX20 is absent or any amino acid.

In certain embodiments of IIIa: X7 is Trp, Bip, Gln, His, Glu(Bzl),4-Phenylbenzylalanine, Tic, Phe[4-(2-aminoethoxy)], Phe(3,4-Cl₂),Phe(4-OMe), 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, α-MeTrp,1,2,3,4-tetrahydro-norharman, Phe(4-CO₂H), Phe(4-CONH₂),Phe(3,4-Dimethoxy), Phe(4-CF₃), ββ-diPheAla, Phe(4-tBu), Glu, Gly, Ile,Asn, Pro, Arg, Thr or Octgly, or a corresponding α-methyl amino acidform of any of the foregoing; X10 is 1-Nal, 2-Nal, Aic, Bip, (D)Cys,Cha, DMT, (D)Tyr, Glu, Phe, His, Trp, Thr, Tic, Tyr, 4-pyridylAla,Octgly a Phe analog or a Tyr analog, or a corresponding α-methyl aminoacid form of any of the foregoing; X11 is 2-Nal, 1-Nal, 2,4-dimethylPhe,Bip, 4-phenylcyclohexyl, Glu(Bzl), 4-Phenylbenzylalanine, Tic,Phe[4-(2-aminoethoxy)], Phe(3,4-Cl₂), Phe(3,4-F₂), βhPhe(4-F),Phe(4-OMe), 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, α-MeTrp,1,2,3,4-tetrahydro-norharman, Phe(4-CO₂H), Phe(4-CONH₂),Phe(3,4-Dimethoxy), Phe(4-CF₃), Phe(2,3-Cl₂), Phe(2,3-F₂), Phe(4-F),4-phenylcyclohexylalanine, α-MePhe, βhPhe, βhTyr, βhTrp, Bip,Nva(5-phenyl), Phe, His, hPhe, Tqa, Trp, Tyr, Phe(4-Me),Trp(2,5,7-tri-tertButyl), Phe(4-OAllyl), Tyr(3-tBu), Phe(4-tBu),Phe(4-guanidino), Phe(4-OBzl), or Octgly, or a corresponding α-methylamino acid form of any of the foregoing; X12 is α-MeLys, α-MeOrn,α-MeLeu, MeLeu, Aib, (D)Ala, (D)Asn, (D)Leu, (D)Asp, (D)Phe, (D)Thr,3-Pal, Aib, β-Ala, βhGlu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg,Asp, Dab, Dap, α-DiethylGly, Glu, Phe, hLeu, hArg, hLeu, Ile, Lys, Leu,Asn, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Arg, Ser, Thr or Tle, or acorresponding α-methyl amino acid form of any of the foregoing; X13 isLys(Ac), (D)Asn, (D)Leu, (D)Thr, (D)Phe, Ala, Aib, α-MeLeu, βAla, βhGlu,βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Arg, Orn, Dab, Dap,α-DiethylGly, Glu, Phe, hLeu, Lys, Leu, Asn, Ogl, Pro, Gln, Asp, Arg,Ser, spiro-pip, Thr, Tba, Tlc, Val or Tyr, or a corresponding α-methylamino acid form of any of the foregoing; X14 is Asn, Glu, Phe, Gly, His,Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic or Tyr, or acorresponding α-methyl amino acid form of any of the foregoing; and X15is Gly, (D)Ala, (D)Asn, (D)Asp, Asn, (D)Leu, (D)Phe, (D)Thr, Ala, AEA,Asp, Glu, Phe, Gly, Lys, Leu, Pro, Gln, Arg or Ser, or a correspondingα-methyl amino acid form of any of the foregoing.

In certain embodiments, X3 is present. In particular embodiments, X3 isGlu, (D)Glu, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, or (D)Gln. Incertain embodiments, it is (D)Arg or (D)Phe.

In particular embodiments, X5 is Gln, Ala, Cys, Cit, Asp, Dab, Dap, Glu,Phe, Gly, His, hCys, Lys, Leu, Met, Asn, N-Me-Ala, N-M-Asn, N-Me-Lys,N-Me-Gln, N-Me-Arg, Orn, Pro, Pen, Gln, Arg, Ser, Thr, or Val.

In particular embodiments, X6 is Thr, Asp, Glu, Phe, Asn, Pro, Arg, Ser,or Thr.

In particular embodiments, X8 is Gln, Glu, Phe, Lys, Asn, Pro, Arg, Val,Thr, or Trp.

In certain embodiments, X10 is a Tyr analog or a Phe analog. Inparticular embodiments, X10 is Phe(4-OMe), Phe(CONH₂) orPhe[4-(2-aminoethoxy)]. In certain embodiments, X10 is a Tyr analog or aPhe analog. In particular embodiments, X10 is Phe(4-OMe) orPhe[4-(2-aminoethoxy)].

In certain embodiments where X10 is a the Phe analog, X10 is selectedfrom hPhe, Phe(4-OMe), α-MePhe, hPhe(3,4-dimethoxy), Phe(4-CONH₂),Phe(4-O-Bzl)), Phe(4-guanadino), Phe(4-tBu), Phe(4-CN), Phe(4-Br),Phe(4-NH₂), Phe(4-F), Phe(3,5 DiF), Phe(CH₂CO₂H), Phe(penta-F),Phe(3,4-Cl₂), Phe(4-CF₃), ββ-diPheAla, Phe(4-N₃) andPhe[4-(2-aminoethoxy)]. In particular embodiments, X10 isPhe[4-(2-aminoethoxy)] or Phe(CONH₂). In particular embodiments, X10 isPhe[4-(2-aminoethoxy)].

In certain embodiments where X10 is a Tyr analog, X10 is selected fromhTyr, N-Me-Tyr, Tyr(3-tBu), Phe(4-OMe) and bhTyr. In particularembodiments, X10 is Phe(4-OMe).

In particular embodiments, X10 is Tyr, Phe(4-OMe), Phe(4-OBzl),Phe(4-OMe), Phe(4-CONH₂), Phe(3,4-Cl₂), Phe(4-tBu), Phe(4-NH₂),Phe(4-Br), Phe(4-CN), Phe(4-carboxy), Phe[4-(2aminoethoxy)] orPhe(4-guanadino). In particular embodiments, X10 is not Tyr.

In certain embodiments, X11 is Trp or a Trp analog. In particularembodiments, X11 is 2-Nal or 1-Nal.

In particular embodiments, the peptide inhibitor of Formula III iscyclized. In certain embodiments, the peptide inhibitor is cyclized viaan intramolecular bond between X4 and X9. In certain embodiments, theintramolecular bond is a thioether bond.

In certain embodiments, the peptide inhibitor of Formula III is linearor not cyclized. In particular embodiments of the linear peptideinhibitor of Formula III, X4 and/or X9 are any amino acid.

In particular embodiments of a peptide inhibitor of Formula III, one ormore, two or more, or all three of X1, X2, and X3 are absent. In certainembodiments, X1 is absent. In certain embodiments, X1 and X2 are absent.In certain embodiments, X1, X2 and X3 are absent.

In particular embodiments of a peptide inhibitor of Formula III, one ormore, two or more, three or more, four or more, or all of X16, X17, X18,X19 and X20 are absent. In particular embodiments of a peptide inhibitorof Formula III, one or more, two or more, three or more, or all of X17,X18, X19 and X20 are absent. In certain embodiments, one or more, two ormore, or all three of X17, X19 and X20 are absent. In certainembodiments, one or more of X1, X2 and X3 are absent; and one or more,two or more, three or more, or four of X17, X18, X19 and X20 are absent.

In particular embodiments of a peptide inhibitor of Formula III, one ofX4 or X9 is Abu, and the other of X4 or X9 is not Abu. In certainembodiments, X4 is Abu and X9 is Cys.

In particular embodiments, a peptide inhibitor of Formula III comprisesone or more, two or more, three or more, or four of the followingfeatures: X5 is Arg or Gln; X6 is Thr; X7 is Trp; and X8 is Gln. Inparticular embodiments, X5 is Gln, X6 is Thr, X7 is Trp, and X8 is Gln.In certain embodiments, X5 is Gln. In certain embodiments, X1, X2 and X3are absent. In certain embodiments, X4 is Abu and X9 is Cys.

In particular embodiments, a peptide inhibitor of Formula III comprisesone or more, two or more, three or more, four or more, five or more, sixor more, or seven of the following features: X10 is Tyr or a Phe analog;X11 is Trp, 2-Nal, 1-Nal, Phe(4-O-Allyl), Tyr(3-tBu), Phe(4-tBu),Phe(4-guanidino), Phe(4-OBzl) or Phe(4-Me); X12 is Arg, hLeu, (D)Asn, orany alpha methyl amino acids including, Aib, α-MeLys, α-MeLeu orα-MeOrn; X13 is Lys, Glu or Lys(Ac); X14 is Phe or Asn; X15 is β-Ala,Gln, Gly, Ser, Ala; and X16 is absent or AEA. In particular embodiments,a peptide inhibitor of Formula III comprises one or more, two or more,three or more, four or more, five or more, six or more, or seven of thefollowing features: X10 is Tyr or a Phe analog; X11 is Trp, 2-Nal,1-Nal, Phe(4-O-Allyl), Tyr(3-tBu), Phe(4-tBu), Phe(4-guanidino),Phe(4-OBzl) or Phe(4-Me); X12 is Arg, hLeu, (D)Asn, or any alpha methylamino acids including, Aib, α-MeLys, α-MeLeu or α-MeOrn; X13 is Lys, Gluor Lys(Ac); X14 is Phe or Asn; X15 is Gly, Ser, Ala; and X16 is absentor AEA. In certain embodiments, the Phe analog is Phe(4-OBzl),Phe(4-OMe), Phe(4-CONH₂), Phe(3,4-Cl₂), Phe(4-tBu), Phe(4-NH₂),Phe(4-Br), Phe(4-CN), Phe(4-carboxy), Phe[4-(2aminoethoxy)] orPhe(4-guanadino). In certain embodiments, X11 is 2-Nal or 1-Nal. Incertain embodiments, X1, X2 and X3 are absent. In certain embodiments,X4 is Abu and X9 is Cys.

In particular embodiments, a peptide inhibitor of Formula III comprisesone or more, two or more, three or more, four or more, five or more, sixor more, or seven of the following features: X10 is Tyr or a Phe analog;X11 is Trp, 2-Nal, 1-Nal, Phe(4-O-Allyl), Tyr(3-tBu), Phe(4-tBu),Phe(4-guanidino), Phe(4-OBzl) or Phe(4-Me); X12 is Arg, hLeu, (D)Asn,4-amino-4-carboxy-tetrahydropyran, Achc Acpc, Acbc, Acvc, Agp, Aib,α-DiethylGly, α-MeLys, α-MeLys(Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal;X13 is Lys, Glu or Lys(Ac); X14 is Phe or Asn; X15 is Gly; and X16 isabsent or AEA. In certain embodiments, the Phe analog is Phe(4-OBzl),Phe(4-OMe), Phe(4-CONH₂), Phe(3,4-Cl₂), Phe(4-tBu), Phe(4-NH₂),Phe(4-Br), Phe(4-CN), Phe(4-carboxy), Phe(4-(2aminoethoxy)) orPhe(4-guanadino). In certain embodiments, X11 is 2-Nal or 1-Nal. Incertain embodiments, X1, X2 and X3 are absent. In certain embodiments,X4 is Abu and X9 is Cys.

In particular embodiments, a peptide inhibitor of Formula III comprisesone or more, two or more, three or more, four or more, five or more, sixor more, seven or more, eight or more, nine or more, ten or more, oreleven of the following features: X5 is Arg or Gln; X6 is Thr; X7 isTrp; X8 is Gln; X10 is a Phe analog; X11 is Trp, 2-Nal, 1-Nal,Phe(4-O-Allyl), Tyr(3-tBu), Phe(4-tBu), Phe(4-guanidino), Phe(Bzl) orPhe(4-Me); X12 is Aib, α-MeLys, α-MeLeu,4-amino-4-carboxy-tetrahydropyran, Achc Acpc, Acbc, Acvc, Agp, Aib,α-DiethylGly, α-MeLys, α-MeLys(Ac), α-Me-Leu, α-MeSer, α-MeVal, α-MeOrn;X13 is Lys, Glu or Lys(Ac); X14 is Phe or Asn; X15 is β-ala, Gly, Ser,Ala; and X16 is absent or AEA. In particular embodiments, a peptideinhibitor of Formula III comprises one or more, two or more, three ormore, four or more, five or more, six or more, seven or more, eight ormore, nine or more, ten or more, or eleven of the following features: X5is Arg or Gln; X6 is Thr; X7 is Trp; X8 is Gln; X10 is a Phe analog; X11is Trp, 2-Nal, 1-Nal, Phe(4-O-Allyl), Tyr(3-tBu), Phe(4-tBu),Phe(4-guanidino), Phe(Bzl) or Phe(4-Me); X12 is Aib, α-MeLys, α-MeLeu orα-MeOrn; X13 is Lys, Glu or Lys(Ac); X14 is Phe or Asn; X15 is Gly, Ser,Ala; and X16 is absent or AEA. In certain embodiments, the Phe analog isPhe(4-OBzl), Phe(4-OMe), Phe[4-(2aminoethoxy)], Phe(4-CONH₂),Phe(3,4-Cl₂), Phe(4-tBu), Phe(4-NH₂), Phe(4-Br), Phe(4-CN), Phe(4-CO₂H),or Phe(4-guanadino). In certain embodiments, X11 is 2-Nal or 1-Nal. Incertain embodiments, X1, X2 and X3 are absent. In certain embodiments,X4 is Abu and X9 is Cys.

In particular embodiments, a peptide inhibitor of Formula III comprisesone or more, two or more, three or more, four or more, five or more, sixor more, seven or more, eight or more, nine or more, ten or more, oreleven of the following features: X5 is Arg or Gln; X6 is Thr; X7 isTrp; X8 is Gln; X10 is Tyr or a Phe analog; X11 is Trp, 2-Nal, 1-Nal,Phe(4-O-Allyl), Tyr(3-tBu), Phe(4-tBu), Phe(4-guanidino), Phe(Bzl) orPhe(4-Me); X12 is Arg, hLeu, (D)Asn, 4-amino-4-carboxy-tetrahydropyran,Achc Acpc, Acbc, Acvc, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac),α-Me-Leu, α-MeSer, α-MeVal; X13 is Lys, Glu or Lys(Ac); X14 is Phe orAsn;

X15 is β-Ala, Asn or Gly; and X16 is absent or AEA. In particularembodiments, a peptide inhibitor of Formula III comprises one or more,two or more, three or more, four or more, five or more, six or more,seven or more, eight or more, nine or more, ten or more, or eleven ofthe following features: X5 is Arg or Gln; X6 is Thr; X7 is Trp; X8 isGln; X10 is Tyr or a Phe analog; X11 is Trp, 2-Nal, 1-Nal,Phe(4-O-Allyl), Tyr(3-tBu), Phe(4-tBu), Phe(4-guanidino), Phe(Bzl) orPhe(4-Me); X12 is Arg, hLeu, (D)Asn, α-MeLys, α-MeLeu or α-MeOrn, Aib;X13 is Lys, Glu or Lys(Ac); X14 is Phe or Asn; X15 is Gly; and X16 isabsent or AEA. In certain embodiments, the Phe analog is Phe(4-OBzl),Phe(4OMe), Phe(4-CONH₂), Phe(3,4-Cl₂), Phe(4-tBu), Phe(4-NH₂),Phe(4-Br), Phe(4-CN), Phe(4-CO₂H), Phe(4-(2-aminoethoxy)) orPhe(4-guanidino). In certain embodiments, X11 is 2-Nal or 1-Nal. Incertain embodiments, X1, X2 and X3 are absent. n certain embodiments, X4is Abu and X9 is Cys.

In certain embodiments, the present invention includes a peptide of 8 to20, 8 to 16 or 8 to 12 amino acids, optionally cyclized, comprising orconsisting of a core sequence of Formula Mb:

Xaa4-Xaa5-Xaa6-Trp-Xaa8-Xaa9-Xaa10-Xaa11  (IIIb)

wherein Xaa4 and Xaa9 are each independently selected from Abu and Cys,wherein Xaa4 and Xaa9 are not both the same; Xaa5, Xaa6 and Xaa8 are anyamino acid residue; Xaa10 is Tyr, a Phe analog or 2-Nal, and Xaa11 is2-Nal or Trp, wherein the peptide inhibits binding of IL-23 to IL-23R.In particular embodiments, Xaa10 is Phe(4-OMe), 2-Nal, orPhe[4-(2-aminoethoxy)]. In one embodiment, Xaa10 is Phe(4-OMe). In oneembodiment, Xaa7 is Phe[4-(2-aminoethoxy)]. In one embodiment, Xaa11 is2-Nal. In certain embodiments, the peptide is cyclized via Xaa4 andXaa9. In particular embodiments, the Phe analog is Phe[4-(2aminoethoxy)]or Phe(4-OMe). In certain embodiments, Xaa4 is Abu and Xaa9 is Cys, andthe peptide is cyclized via Xaa4 and Xaa9. In particular embodiments,the peptide is a peptide inhibitor of Formula III, and wherein incertain embodiments, X1, X2 and X3 are absent. In particularembodiments, the peptide inhibits the binding of IL-23 to IL-23R. Incertain embodiments, a peptide of Formula IIIb comprises a Glu, (D)Glu,Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, or (D)Gln bound to Xaa4. Incertain embodiments, it is (D)Arg or (D)Phe.

In certain embodiments, the present invention includes a peptide of 8 to20, 8 to 16 or 8 to 12 amino acids, optionally cyclized, comprising orconsisting of a core sequence of Formula IIIc:

Abu-Xaa5-Xaa6-Trp-Xaa8-Cys-[Phe(4-0Me)]-(2-Nal)  (IIIc)

wherein Xaa5, Xaa6 and Xaa8 are any amino acid residue; and wherein thepeptide inhibits binding of IL-23 to IL-23R. In certain embodiments, thepeptide is cyclized via Abu at Xaa4 and Cys at Xaa9. In certainembodiments, the peptide is a peptide inhibitor of Formula III, andwherein in certain embodiments, X1, X2 and X3 are absent. In particularembodiments, the peptide inhibits the binding of IL-23 to IL-23R. Incertain embodiments, a peptide of Formula IIIc comprises a Glu, (D)Glu,Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, or (D)Gln bound to Abu. Incertain embodiments, it is (D)Arg or (D)Phe.

In certain embodiments, the present invention includes a peptide of 8 to20, 8 to 16 or 8 to 12 amino acids, optionally cyclized, comprising orconsisting of a core sequence of Formula IIId:

Abu-Xaa5-Xaa6-Trp-Xaa8-Cys-Xaa10-Trp  (IIId)

wherein Xaa5, Xaa6 and Xaa8 are any amino acid residue; Xaa10 is amodified Phe; and

wherein the peptide inhibits binding of IL-23 to IL-23R. In particularembodiments, the modified Phe is Phe(4-tBu), Phe(4-guanidino),Phe[4-(2-aminoethoxy)], Phe(4-CO₂H), Phe(4-CN), Phe(4-Br), Phe(4-NH₂),PHe(CONH₂) or Phe(4-Me). In particular embodiments, the modified Phe isPhe(4-tBu), Phe(4-guanidino), Phe[4-(2-aminoethoxy)], Phe(4-CO₂H),Phe(4-CN), Phe(4-Br), Phe(4-NH₂), or Phe(4-Me). In one embodiment, Xaa10is Phe[4-(2-aminoethoxy)] or Phe(4-OMe). In one embodiment, Xaa10 isPhe[4-(2-aminoethoxy)]. In certain embodiments, the peptide is cyclizedvia Abu at Xaa4 and Cys at Xaa9. In certain embodiments, the peptide isa peptide inhibitor of Formula III, and wherein in certain embodiments,X1, X2 and X3 are absent. In particular embodiments, the peptideinhibits the binding of IL-23 to IL-23R. In certain embodiments, apeptide of Formula IIId comprises a Glu, (D)Glu, Arg, (D)Arg, Phe,(D)Phe, 2-Nal, Thr, Leu, or (D)Gln bound to Abu. In certain embodiments,it is (D)Arg or (D)Phe.

In certain embodiments, the present invention includes a peptide,optionally 8 to 20, 8 to 16 or 8 to 12 amino acids, optionally cyclized,comprising or consisting of a core sequence of Formula IIIe:

Abu-Xaa5-Xaa6-Trp-Xaa8-Cys-Phe[4-(2-aminoethoxy)]-[2-Nal]  (IIIe)

wherein Xaa5, Xaa6 and Xaa8 are any amino acid residue. In certainembodiments, the peptide is cyclized via Abu at Xaa4 and Cys at Xaa9. Incertain embodiments, the peptide is a peptide inhibitor of Formula III,and wherein in certain embodiments, X1, X2 and X3 are absent. Inparticular embodiments, the peptide inhibits the binding of IL-23 toIL-23R. In certain embodiments, a peptide of Formula IIIb comprises aGlu, (D)Glu, Arg, (D)Arg, Phe, (D)Phe, 2-Nal, Thr, Leu, or (D)Gln boundto Abu. In certain embodiments, it is (D)Arg or (D)Phe.

In one embodiment, Xaa5 and Xaa8 is Gln. In one embodiment, Xaa6 is Thr.In certain embodiments, the peptide is cyclized via Abu at Xaa4 and Cysat Xaa9.

In particular embodiments of a peptide inhibitor of Formula III, thepeptide inhibitor has a structure shown in any of Tables 5A-5C orcomprises an amino acid sequence set forth in Tables 5A-5C.

Illustrative Peptide Inhibitors Containing Cyclic Amides

In certain embodiments, the present invention includes a peptideinhibitor of an interleukin-23 receptor, wherein the peptide inhibitorhas the structure of Formula IV:

R¹—X—R²  (IV)

or a pharmaceutically acceptable salt or solvate thereof,

wherein R¹ is a bond, hydrogen, an C1-C6 alkyl, a C6-C12 aryl, a C6-C12aryl C1-C6 alkyl, a C1-C20 alkanoyl, and including PEGylated versionsalone or as spacers of any of the foregoing;

R² is a bond, OH or NH₂; and

X is an amino acid sequence of 8 to 20 amino acids, comprising orconsisting of the sequence of Formula IVa:

X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (IVa)

wherein

X1 is absent or any amino acid;X2 is absent or any amino acid;X3 is absent or any amino acid;

X4 is Dap, Dab, Glu, Asp, (D)-Asp or (D)-Dab;

X5 is Gln, Ala, Cys, Cit, Asp, Dab, Dap, Glu, Phe, Gly, His, hCys, Lys,Leu, Met, Asn, N-Me-Ala, N-M-Asn, N-Me-Lys, N-Me-Gln, N-Me-Arg, Orn,Pro, Pen, Gln, Arg, Ser, Thr, or Val;

X6 is Thr, Asp, Glu, Phe, Asn, Pro, Arg, Ser, or Thr; X7 is Trp, Glu,Gly, Ile, Asn, Pro, Arg, Thr or OctGly; X8 is Gln, Glu, Phe, Lys, Asn,Pro, Arg, Thr, or Trp; X9 is Dap, Dab, Glu, Asp, (D)-Asp or (D)-Dab;

X10 is Tyr(OMe)Phe(4-OMe), 1-Nal, 2-Nal, Aic, α-MePhe, Bip, (D)Cys, Cha,DMT, (D)Tyr), Glu, Phe, His, hPhe(3,4-dimethoxy), hTyr, N-Me-Tyr, Trp,Phe(4-CONH₂), Phe(4-phenoxy), Thr, Tic, Tyr, Tyr(3-tBu), Phe(4-tBu),Phe(4-CN), Phe(4-Br), Phe(4-NH₂), Phe(4-F), Phe(3,5-F₂), Phe(penta-F),Phe(3,4-Cl₂), Phe(4-CF₃), Bip, Cha, 4-pyridylalanine, βhTyr, OctGly,Phe(4-N₃), Phe(4-Br) or Phe[4-(2-aminoethoxy)];X11 is 2-Nal, 1-Nal, 2,4-dimethylPhe, Bip, Phe(3,4-Cl₂), Phe(3,5-F₂),Phe(4-CONH₂), Phe(4-F), 4-phenylcyclohexylalanine, Phe(4-CF₃), α-MePhe,βhPhe, βhTyr, βhTrp, BIP, Nva(5-phenyl), Phe, His, hPhe, Tic, Tqa, Trp,Tyr, Phe(4-OMe), Phe(4-Me), Trp(2,5,7-tri-tertButyl), Phe(4-OAllyl),Tyr(3-tBu), Phe(4-tBu), Phe(4-guanidino), Tyr(Bzl), or OctGly;X12 is α-MeLys, α-MeOrn, α-MeLeu, Aib, (D)Ala, (D)Asn, (D)Leu, (D)Asp,(D)Phe, (D)Thr, 3-Pal, Aib, β-Ala, β-Glu, βhAla, βhLeu, βhVal,β-spiro-pip, Cha, Chg, Asp, Dab, Dap, α-DiethylGly, Glu, Phe, hLeu,hArg, hLeu, Ile, Lys, Leu, Asn, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln,Arg, Ser, Thr Tle, 4-amino-4-carboxy-tetrahydropyran, Achc Acpc, Acbc,Acvc, α-DiethylGly, α-MeLys, α-MeLys(Ac), α-Me-Leu, α-MeSer, α-MeVal;X13 is Lys(Ac), (D)Asn, (D)Leu, (D)Thr, (D)Phe, Ala, Aib, α-MeLeu, Aib,β-Ala, β-Glu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Dab, Dap,α-DiethylGly, Glu, Phe, hLeu, Lys, Lys(Ac), Leu, Asn, Ogl, Pro, Gln,Arg, Ser, β-spiro-pip, Thr, Tba, Tlc, Val or Tyr;

X14 is Asn, Glu, Phe, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser,Thr, Tic or Tyr;

X15 is β-ala, Asn, Gly, (D)Ala, (D)Asn, (D)Asp, (D)Leu, (D)Phe, (D)Thr,Ala, AEA, Asp, Glu, Phe, Gly, Lys, Leu, Pro, Gln, Arg or Ser;X16 is absent, Gly, Ala, Asp, Ser, Pro, Asn or Thr;X17 is absent, Glu, Ser, Gly or Gln;X18 is absent or any amino acid;X19 is absent or any amino acid; andX20 is absent or any amino acid.

In certain embodiments of IVa: X12 is α-MeLys, α-MeOrn, α-MeLeu, Aib,(D)Ala, (D)Asn, (D)Leu, (D)Asp, (D)Phe, (D)Thr, 3-Pal, Aib, β-Ala,β-Glu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Dab, Dap,α-DiethylGly, Glu, Phe, hLeu, hArg, hLeu, Ile, Lys, Leu, Asn, N-MeLeu,N-MeArg, Ogl, Orn, Pro, Gln, Arg, Ser, Thr or Tle; X13 is Lys(Ac),(D)Asn, (D)Leu, (D)Thr, (D)Phe, Ala, Aib, α-MeLeu, Aib, β-Ala, β-Glu,βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Dab, Dap, α-DiethylGly,Glu, Phe, hLeuLys, Leu, Asn, Ogl, Pro, Gln, Arg, Ser, β-spiro-pip, Thr,Tba, Tlc, Val or Tyr; X14 is Asn, Glu, Phe, Gly, His, Lys, Leu, Met,Asn, Pro, Gln, Arg, Ser, Thr, Tic or Tyr; and X15 is Gly, (D)Ala,(D)Asn, (D)Asp, (D)Leu, (D)Phe, (D)Thr, Ala, AEA, Asp, Glu, Phe, Gly,Lys, Leu, Pro, Gln, Arg or Ser.

In particular embodiments of a peptide inhibitor of Formula (IV): X5 isCys, Cit, Asp, Dab, Dap, Gly, His, hCys, Lys, Met, Asn, N-Me-Ala,N-Me-Asn, N-Me-Lys, N-Me-Gln, N-Me-Arg, Orn, Pro, Pen, Gln, Val; X6 isGlu, Arg, Ser; X7 is Trp, Glu, Gly, Ile, Asn, Pro, Arg, Thr or OctGly;X8 is Phe, Asn, Pro, Arg, Thr, Trp; X10 is Phe(4-OMe), 1-Nal, 2-Nal,Aic, α-MePhe, Bip, (D)Cys, Cha, DMT, (D)Tyr, Glu, His,hPhe(3,4-dimethoxy), hTyr, N-Me-Tyr, Trp, Phe(4-CONH₂), Phe-(4-phenoxy),Thr, Tic, Tyr(3-tBu), Phe(4-tBu), Phe(4-CN), Phe(4-Br), Phe(4-NH₂),Phe(4-F), Phe(3,5-F₂), PheCH₂CO₂H, Phe(penta-F), Phe(3,4-Cl₂),Phe(4-CF₃), Bip, Cha, 4-PyridylAlanine, βhTyr, OctgGly, Tyr(4-N₃),Phe(4-Br), Phe[4-(2-aminoethoxy)]; X11 is 2-Nal, 1-Nal, 2,4-dimethylPhe,Bip, Phe(3,4-Cl₂), Phe(3,5-F₂), Phe(4-CONH₂), Phe(4-F),4-phenylcyclohexyl, Phe(4-CF₃), α-MePhe, Nal, βhPhe, βhTyr, βhTrp, BIP,Nva(5-phenyl), Phe, His, hPhe, Tic, Tqa, Tyr, Phe(4-OMe), Phe(4-Me),Tyr(2,5,7-tri-tert-Butyl), Phe(4-OAllyl), Phe(3-tBu), Phe(4-tBu),Phe(4-guanidino), Tyr(Bzl), OctGly; X12 is α-Me-Lys, D-Ala, (D)Asn,(D)Asp, (D)Leu, (D)Phe, (D)Tyr, Aib, α-MeLeu, α-MeOrn, Aib, β-Ala,βhAla, βhArg, βhLeu, βhVal, β-spiro-pip, Glu, hArg, Ile, Lys, N-MeLeu,N-MeArg, Ogl, Orn, Pro, Gln, Ser, Thr, Tle,4-amino-4-carboxy-tetrahydropyran, Achc Acpc, Acbc, Acvc, α-DiethylGly,α-MeLys(Ac)-α-MeSer, α-MeVal; X13 is Lys, Lys(Ac), (D)Asn, (D)Leu,(D)Phe, (D)Thr, Ala, α-MeLeu, Aib, 13-Ala, β-Glu, βhLeu, βhVal,β-spiro-pip, Cha, Chg, Asp, Dab, Dap, α-DiethylGly, hLeu, Asn, Ogl, Pro,Gln, Ser, Thr, Tba, Tle; X14 is Glu, Gly, His, Lys, Leu, Met, Asn, Pro,Gln, Arg, Ser, Thr, Tic; X15 is (D)Ala, (D)Asn, (D)Asp, (D)Leu, (D)Phe,(D)Thr, Aea, Asp, Glu, Phe, Gly, Lys, Leu, Pro, Asn, Arg or 13-Ala; X16is Gly, Ser, Pro, Asn, Thr; or X17 is Glu, Ser, Gly, Gln.

In particular embodiments of a peptide inhibitor of Formula (IV): X5 isCys, Cit, Asp, Dab, Dap, Gly, His, hCys, Lys, Met, Asn, N-Me-Ala,N-Me-Asn, N-Me-Lys, N-Me-Gln, N-Me-Arg, Orn, Pro, Pen, Gln, Val; X6 isGlu, Arg, Ser; X7 is Trp, Glu, Gly, Ile, Asn, Pro, Arg, Thr or OctGly;X8 is Phe, Asn, Pro, Arg, Thr, Trp; X10 is Phe(4-OMe), 1-Nal, 2-Nal,Aic, α-MePhe, Bip, (D)Cys, Cha, DMT, (D)Tyr, Glu, His,hPhe(3,4-dimethoxy), hTyr, N-Me-Tyr, Trp, Phe(4-CONH₂), Phe-(4-phenoxy),Thr, Tic, Tyr(3-tBu), Phe(4-tBu), Phe(4-CN), Phe(4-Br), Phe(4-NH₂),Phe(4-F), Phe(3,5-F₂), PheCH₂CO₂H, Phe(penta-F), Phe(3,4-Cl₂),Phe(4-CF₃), Bip, Cha, 4-PyridylAlanine, βhTyr, OctgGly, Tyr(4-N₃),Phe(4-Br), Phe[4-(2-aminoethoxy)]; X11 is 2-Nal, 1-Nal, 2,4-dimethylPhe,Bip, Phe(3,4-Cl₂), Phe(3,5-F₂), Phe(4-CONH₂), Phe(4-F),4-phenylcyclohexyl, Phe(4-CF₃), α-MePhe, Nal, βhPhe, βhTyr, βhTrp, BIP,Nva(5-phenyl), Phe, His, hPhe, Tic, Tqa, Tyr, Phe(4-OMe), Phe(4-Me),Tyr(2,5,7-tri-tert-Butyl), Phe(4-OAllyl), Phe(3-tBu), Phe(4-tBu),Phe(4-guanidino), Tyr(Bzl), OctGly; X12 is α-Me-Lys, D-Ala, (D)Asn,(D)Asp, (D)Leu, (D)Phe, (D)Tyr, Aib, α-MeLeu, α-MeOrn, Aib, β-Ala,βhAla, βhArg, βhLeu, βhVal, β-spiro-pip, Glu, hArg, Ile, Lys, N-MeLeu,N-MeArg, Ogl, Orn, Pro, Gln, Ser, Thr, Tle; X13 is Lys(Ac), (D)Asn,(D)Leu, (D)Phe, (D)Thr, Ala, α-MeLeu, Aib, β-Ala, β-Glu, βhLeu, βhVal,β-spiro-pip, Cha, Chg, Asp, Dab, Dap, α-DiethylGly, hLeu, Asn, Ogl, Pro,Gln, Ser, Thr, Tba, Tle; X14 is Glu, Gly, His, Lys, Leu, Met, Asn, Pro,Gln, Arg, Ser, Thr, Tic; X15 is (D)Ala, (D)Asn, (D)Asp, (D)Leu, (D)Phe,(D)Thr, Aea, Asp, Glu, Phe, Gly, Lys, Leu, Pro, Arg; X16 is Gly, Ser,Pro, Asn, Thr; or X17 is Glu, Ser, Gly, Gln.

In certain embodiments, the peptide inhibitor is cyclized. In particularembodiments, the peptide is cyclized through an intramolecular bondbetween X4 and X9. In particular embodiments, the intramolecular bond isan amide bond.

In certain embodiments, the peptide inhibitor is linear or not cyclized.

In particular embodiments of a peptide inhibitor of Formula IV, one ormore, two or more, or all three of X1, X2, and X3 are absent.

In certain embodiments, X3 is Glu, (D)Glu, Arg, (D)Arg, Phe, (D)Phe,2-Nal, Thr, Leu, or (D)Gln. In certain embodiments, X3 is (D)Arg or(D)Phe.

In particular embodiments of a peptide inhibitor of Formula IV, one ormore, two or more, or all three of X17, X19 and X20 are absent.

In particular embodiments of a peptide inhibitor of Formula IV, X4 isDap, Dab, or (D)Dab, and X9 is Glu, (D)Asp, or Asp. In particularembodiments of a peptide inhibitor of Formula I, X4 is Glu, (D)Asp orAsp, and X9 is Dab, Dap or (D)Dab.

In particular embodiments of a peptide inhibitor of Formula IV, X18 is(D)-Lys. In certain embodiments, X17 is absent and X18 is (D)-Lys.

In particular embodiments of a peptide inhibitor of Formula IV, thepeptide inhibitor includes one or more, two or more, three or more, orall four of the following features: X5 is Gln; X6 is Thr; X7 is Trp; andX8 is Gln.

In particular embodiments of a peptide inhibitor of Formula IV, thepeptide inhibitor includes one or more, two or more, three or more, fouror more, five or more, six or more, or seven of the following features:X10 is Tyr, Phe[4-(2-aminoethoxy)], Phe(4-CONH₂) or Phe(4-OMe); X11 is2-Nal or Trp; X12 is 4-amino-4-carboxy-tetrahydropyran, Achc Acpc, Acbc,Acvc, Aib, α-DiethylGly, α-MeLys, α-MeLys(Ac), α-Me-Leu, α-MeOrn,α-MeSer, α-MeVal, or Arg; X13 is Glu or Lys(Ac); X14 is Asn; X15 is Gly,Asn, or β-Ala; and X16 is AEA. In particular embodiments of a peptideinhibitor of Formula IV, the peptide inhibitor includes one or more, twoor more, three or more, four or more, five or more, six or more, orseven of the following features: X10 is Tyr; X11 is Trp; X12 is Arg; X13is Glu; X14 is Asn; X15 is Gly; and X16 is AEA.

In particular embodiments of a peptide inhibitor of Formula IV, thepeptide inhibitor includes one or more, two or more, three or more, fouror more, five or more, six or more, seven or more, eight or more, nineor more ten or more or all of the following features: X5 is Gln; X6 isThr; X7 is Trp; X8 is Gln; X10 is Tyr; X11 is Trp; X12 is Arg; X13 isGlu or Lys(Ac); X14 is Asn; X15 is Gly; and X16 is AEA. In particularembodiments of a peptide inhibitor of Formula IV, the peptide inhibitorincludes one or more, two or more, three or more, four or more, five ormore, six or more, seven or more, eight or more, nine or more ten ormore or all of the following features: X5 is Gln; X6 is Thr; X7 is Trp;X8 is Gln; X10 is Tyr; X11 is Trp; X12 is Arg; X13 is Glu; X14 is Asn;X15 is Gly; and X16 is AEA.

In certain embodiments of a peptide inhibitor of Formula IV, the peptideis cyclized via X4 and X9; X5, X6, X7 and X8 are Gln, Thr, Trp, and Gln,respectively; and X10, X11, X12, X13, X14, X15, and X16 are Tyr, Trp,Arg, Glu, Asn, Gly, and AEA, respectively.

In certain embodiments, the present invention includes a peptide of 8 to20 amino acids, optionally cyclized, comprising or consisting of havinga core sequence comprising:

Xaa4-Xaa5-Xaa6-Trp-Xaa8-Xaa9-[Phe(4-OMe)]-[2-Nal]  (Formula IVb)

wherein Xaa4 and Xaa9 are each independently selected from Dap, Dab,Glu, Asp, (D)-Asp and (D)-Dab, wherein Xaa4 and Xaa9 are capable offorming an intramolecular bond, e.g., a cyclic amide; and Xaa5, Xaa6 andXaa8 are any amino acid residue, wherein the peptide inhibits binding ofIL-23 to IL-23R. In particular embodiments, the peptide inhibitor is apeptide inhibitor of Formula IV. In particular embodiments, the peptideinhibits the binding of IL-23 to IL-23R.

In certain embodiments, of a peptide inhibitor of Formula IV, thepeptide inhibitor has a structure shown in Table 7 or comprises an aminoacid sequence set forth in Table 7.

Optional Characteristics of Peptide Inhibitors

Any of the peptide inhibitors of the present invention (e.g., those ofFormula I (Ia-It), II, III, IV or V) may be further defined, e.g., asdescribed below. It is understood that each of the further definingfeatures described herein may be applied to any peptide inhibitors wherethe amino acids designated at particular positions allow the presence ofthe further defining feature.

In certain embodiments of any of the peptide inhibitors describedherein, the peptide inhibitor is cyclized.

In certain embodiments of any of the peptide inhibitors describedherein, the peptide inhibitor or monomer subunit thereof is linear ornot cyclized. In certain embodiments where the peptide is linear or notcyclized, X4 and X9 can be any amino acid.

In certain embodiments, the peptide inhibitor is cyclized, e.g., throughX4 and X9.

In various embodiments, R¹ is a bond, hydrogen, a C1-C6 alkyl, a C6-C12aryl, a C6-C12 aryl C1-C6 alkyl, or a C1-C20 alkanoyl, and includingPEGylated versions alone or as spacers of any of the foregoing, e.g.,acetyl. It is understood that the R¹ may replace or be present inaddition to the typical amine group located at the amino terminus of apeptide. It is further understood that R¹ may be absent. In certainembodiments, the peptide inhibitor comprises an N-terminus selected fromhydrogen, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12 aryl C1-C6 alkyl, or aC1-C20 alkanoyl, and including PEGylated versions alone or as spacers ofany of the foregoing, e.g., acetyl. In particular embodiments of any ofthe peptide inhibitors described herein, R¹ is hydrogen. In certainembodiments, R¹ is a bond, e.g., a covalent bond.

In certain embodiments of any of the peptide inhibitors having any ofthe various Formulas set forth herein, R¹ is selected from methyl,acetyl, formyl, benzoyl, trifluoroacetyl, isovaleryl, isobutyryl,octanyl, and the conjugated amides of lauric acid, hexadecanoic acid,and γ-Glu-hexadecanoic acid. In one embodiment, R¹ is pGlu. In certainembodiments, R¹ is hydrogen. In particular embodiments, R¹ is acetyl,whereby the peptide inhibitor is acylated at its N-terminus, e.g., tocap or protect an N-terminal amino acid residue, e.g., an N-terminal Penor Abu residue.

In certain embodiments of any of the peptide inhibitors describedherein, R¹ is an acid. In certain embodiments, R¹ is an acid selectedfrom acetic acid, formic acid, benzoic acid, trifluoroacetic acid,isovaleric acid, isobutyric acid, octanoic acid, lauric acid,hexadecanoic acid, 4-Biphenylacetic acid, 4-fluorophenylacetic acid,gallic acid, pyroglutamic acid, cyclopentanepropionic acid, glycolicacid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinicacid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamicacid, mandelic acid, 4-methylbicyclo(2.2.2)-oct-2-ene-1-carboxylic acid,glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid,tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamicacid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid,an alkylsulfonic acid and an arylsulfonic acid.

In particular embodiments, R¹ is an alkylsulfonic acid selected frommethanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,and 2-hydroxyethanesulfonic acid.

In particular embodiments, R¹ is an arylsulfonic acid selected frombenzenesulfonic acid, 4-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, 4-toluenesulfonic acid, and camphorsulfonicacid.

In some embodiments, wherein a peptide of the present inventioncomprises a conjugation to an acidic compound such as, e.g., isovalericacid, isobutyric acid, valeric acid, and the like, the presence of sucha conjugation is referenced in the acid form. So, for example, but notto be limited in any way, instead of indicating a conjugation ofisovaleric acid to a peptide by referencing isovaleroyl (e.g.,isovaleroyl-[Pen]-QTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂(SEQ ID NO: 262), in some embodiments, the present applicationreferences such a conjugation as isovalericacid-[Pen]-QTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂(SEQ ID NO: 263). Reference to the conjugation in its acid form isintended to encompass the form present in the peptide inhibitor.

In certain embodiments, the peptide inhibitor comprises a C-terminus(e.g., R²) selected from a bond, OH or NH₂. In certain embodiments, R²is a bond. In various embodiments of any of the peptide inhibitorshaving any of the various Formulas set forth herein, R² is OH or NH₂. Itis understood that the R² may replace or be present in addition to thecarboxyl group typically located at the carboxy terminus of a peptide.It is further understood that R² may be absent.

In particular embodiments of any of the peptide inhibitors having any ofthe various Formulae set forth herein, X comprises or consists of 7 to35 amino acid residues, 8 to 35 amino acid residues, 9 to 35 amino acidresidues, 10 to 35 amino acid residues, 7 to 25 amino acid residues, 8to 25 amino acid residues, 9 to 25 amino acid residues, 10 to 25 aminoacid residues, 7 to 20 amino acid residues, 8 to 20 amino acid residues,9 to 20 amino acid residues, 7 to 18 amino acid residues, 8 to 18 aminoacid residues, 9 to 18 amino acid residues, or 10 to 18 amino acidresidues.

In certain embodiments of any of the Formulae set forth herein, X eitheror both does not comprise or does not consist of an amino acid sequenceset forth in US Patent Application Publication No. US2013/0029907. Incertain embodiments of any of the Formulae set forth herein, X either orboth does not comprise or does not consist of an amino acid sequence setforth in US Patent Application Publication No. US2013/0172272.

In certain embodiments of any of the peptide inhibitors describedherein, the peptide inhibitor, or each monomer subunit thereof,comprises or consists of at least 3, at least 4 at least 5, at least 6,or at least 7 amino acid residues carboxy terminal of the X9 amino acidresidue. In particular embodiments of any of the peptide inhibitorsdescribed herein, the peptide inhibitor comprises 3 to 11, 3 to 10, 3 to9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 3, 4, 5, 6, 7, 8, 9, 10, or11 amino acid residues carboxy terminal of the X9 amino acid residue.

In certain embodiments of any of the peptide inhibitors describedherein, the peptide inhibitor, or each monomer subunit thereof,comprises or consists of 4 amino acid residues between X4 and X9. In oneembodiment, both X4 and X9 are cysteines.

In certain embodiments of any of the peptide inhibitors describedherein, the peptide inhibitor, or each monomer subunit thereof,comprises the amino acid sequence motif, W-X-X—Y—W, e.g., at positionsX7-X11. In certain embodiments, the peptide inhibitor, or each monomersubunit thereof, comprises the amino acid sequence motif,C-X-X-W-X-C-Y-W (SEQ ID NO: 264), e.g., at positions X4-X11. In certainembodiments, the peptide inhibitor, or each monomer subunit thereof,comprises the amino acid sequence motif, Pen-X-X-W-X-Pen-Y-W, e.g., atpositions X4-X11. In certain embodiments of any of the peptideinhibitors described herein, the peptide inhibitor, or both monomersubunit thereof, does not comprise the amino acid sequence motif,W-X-X—Y—W, e.g., at positions X7-X11, where X is any amino acid.

In certain embodiments of any of the Formula or peptide inhibitorsdescribed herein, the peptide inhibitor comprises one or more amino acidresidues N-terminal to X4. In particular embodiments, X3 is present. Incertain embodiments, X3 is Glu, (D)Glu, Arg, (D)Arg, Phe, (D)Phe, 2-Nal,Thr, Leu, or (D)Gln. In certain embodiments, X3 is (D)Arg or (D)Phe.

In particular embodiments of any of the Formula or peptide inhibitorsdescribed herein, the peptide inhibitor comprises an amino acid at X2.In particular embodiments, X2 is Glu, (D)Asp, Arg, (D)Arg, Phe, (D)Phe,2-Nal, Thr, Leu, (D)Gln, or (D)Asn. In certain embodiments, X2 and X3are present. In particular embodiments, X2 is Glu, (D)Asp, Arg, (D)Arg,Phe, (D)Phe, 2-Nal, Thr, Leu, (D)Gln, or (D)As, and X3 is (D)Arg.

In certain embodiments, a peptide inhibitor of the present invention, orone or both monomer subunits thereof, comprises, optionally at itsC-terminus, one of the following amino acid sequences:

ENG; ENN; [4-amino-4-carboxy-tetrahydropyran]-ENN; [Lys(Ac)]-NN; (SEQ IDNO: 265) [α-MeLys]-ENG; (SEQ ID NO: 266) [α-MeLys]-[Lys(Ac)]-NN; (SEQ IDNO: 267) [α-MeLeu]-[Lys(Ac)]-NN (SEQ ID NO: 268) [α-MeLeu]-ENG;[α-MeOrn]-[Lys(Ac)]-NG; (SEQ ID NO: 269) [α-MeLeu]-ENG;Aib-[Lys(Ac)]-NG; Aib-[Lys(Ac)]-NN; NG-[AEA]-[(D)-Lys];[Dapa]-NG-[AEA]-[(D)-Lys]; [Orn]-NG-[AEA]-[(D)-Lys]; (SEQ ID NO: 270)[α-MeLys]-ENN; [4-amino-4-carboxy-tetrahydropyran]-[Lys(Ac)]-NN;[Achc]-[Lys(Ac)]-NN; or [Acpc]-[Lys(Ac)]-NN.

In particular embodiments, one of these amino acid sequences constitutesthe terminal C-terminal amino acids of the peptide. In particularembodiment, these amino acid sequences correspond to X13-X15 or X12-X15or X14-X16 or X13-X17.

In certain embodiments, a peptide inhibitor of the present invention, orone or both monomer subunits thereof, comprises, optionally at itsC-terminus, one of the following amino acid sequences:

(SEQ ID NO: 271) WQCY-[2-Nal]-[α-MeLys]; (SEQ ID NO: 272)WQC-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]; (SEQ ID NO: 273)WQC-[Phe(4-OMe)]-[2-Nal]-[Aib]; (SEQ ID NO: 274)WQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys];W-Xaa8-C-Phe[4-(2-aminoethoxy)]-[2-Nal];W-Xaa8-C-Phe[4-(2-aminoethoxy)]-[1-Nal];W-Xaa8-C-Phe[4-(2-aminoethoxy)]; or

W-Xaa8-C-[Phe(4-OCH₃)]. In particular embodiments, one of these aminoacid sequences constitutes the terminal C-terminal amino acids of thepeptide. In particular embodiment, these amino acid sequences correspondto X7 to X12 or X7 to X11 or X7 to X10.

In certain embodiments of any of the peptide inhibitors describedherein, including both peptide monomer inhibitors and monomer subunitsof peptide dimer inhibitors, the peptide monomer inhibitor or monomersubunit is cyclized via a peptide bond between its N-terminal amino acidresidue and its C-terminal amino acid residue. In particularembodiments, the peptide inhibitor (or monomer subunit thereof)comprises both an intramolecular bond between X4 and X9 and a peptidebond between its N-terminal amino acid residue and its C-terminal aminoacid residue. In certain embodiments, the intramolecular bond is any ofthose described herein, e.g., a disulfide bond or a thioether bond.

In certain embodiments, the present invention includes a peptideinhibitor that comprises a core consensus sequence selected from one ofthe following (shown in N-terminal to C-terminal direction):

-   -   X1-X2-X3-Pen-X5-X6-W-X8-Pen-X10-X11-X12-X13-X14-X15;    -   Pen-X5-X6-W-Q-Pen;    -   Pen-X5-X6-W-X8-Pen;    -   Pen-X5-X6-W-X8-Pen-[Phe(4-CONH2)]; and    -   Pen-X5-X6-W-X8-Pen-[Phe[4-(2-aminoethoxy)]],        wherein the Pen residues are joined by an intramolecular bond,        e.g., disulphide bond. X1, X2, X3, X5, X6, X8, X10, X11, X12,        X13, X14, and X15 may be any amino acid. In some embodiment X5        is Arg, Asn, Gln, Dap, Orn; X6 is Thr or Ser; and X8 is Gln,        Val, Phe, Glu, Lys. In particular embodiments, X1, X2, X3, X5,        X6, X8, X10, X11, X12, X13, X14, and X15 are defined as        described in any of the various Formulas and peptide inhibitors        described herein.

In certain embodiments, the present invention includes a peptideinhibitor that comprises a core consensus sequence selected from one ofthe following (shown in N-terminal to C-terminal direction):

-   -   X1-X2-X3-Abu-X5-X6-W-X8-C-X9-X10-X11-X12-X13-X14-X15;    -   Abu-X5-X6-W-Q-C;    -   Abu-X5-X6-W-X8-C;    -   Abu-X5-X6-W-X8-C-[Phe(4-CONH2)]; and    -   Abu-X5-X6-W-X8-C-[Phe[4-(2-aminoethoxy)]],        where Abu and C are linked through a intra moleculer thiother        bond. X1, X2, X3, X5, X6, X8, X10, X11, X12, X13, X14, and X15        may be any amino acid. In some embodiment X5 is Arg, Asn, Gln,        Dap, Orn; X6 is Thr or Ser; and X8 is Gln, Val, Phe, Glu, Lys.        In particular embodiments, X1, X2, X3, X5, X6, X8, X10, X11,        X12, X13, X14, and X15 are defined as described in any of the        various Formulas and peptide inhibitors described herein.

In certain embodiments, any of the peptide inhibitors described hereinmay be further cyclized via a peptide bond between its N-terminal aminoacid residue and its C-terminal amino acid residue. In particularembodiments, the peptide inhibitor comprises a peptide bond between X3or X4 and any one of X9, X10, X11, X12, X13, X14, X15, X16, X17, X18,X19 or X20. In particular embodiments, peptide inhibitors of the presentinvention comprise a peptide bond between their N-terminal andC-terminal amino acid residues, and they also comprise an intramolecularbond between X4 and X9. In certain embodiments, the intramolecular bondis a disulfide bond, a thioether bond, a lactam bond or any of the otherbonds described herein.

Peptide Dimers

In certain embodiments, the present invention includes dimers of themonomer peptide inhibitors described herein, including dimers of any ofthe monomer peptide inhibitors described herein, e.g., any of FormulasI, II, III, or IV, or shown in any of Tables 3A-3H, 4A, 4B, 5A-5C, 6, 7,8, 9, 10, 11, 12, 13, 14 or 15. These dimers fall within the scope ofthe general term “peptide inhibitors” as used herein. Illustrativedimers of the present invention are also shown in Table 3F and 4A, whichindicate the dimerized monomer subnits in brackets followed by thelinker. Unless otherwise indicated, the subunits are linked via theirC-termini. The term “dimer,” as in a peptide dimer, refers to compoundsin which two peptide monomer subinits are linked. A peptide dimerinhibitor of the present invention may comprise two identical monomersubunits, resulting in a homodimer, or two non-identical monomersubunits, resulting in a heterodimer. A cysteine dimer comprises twopeptide monomer subunits linked through a disulfide bond between acysteine residue in one monomer subunit and a cysteine residue in theother monomer subunit.

In some embodiments, the peptide inhibitors of the present invention maybe active in a dimer conformation, in particular when free cysteineresidues are present in the peptide. In certain embodiments, this occurseither as a synthesized dimer or, in particular, when a free cysteinemonomer peptide is present and under oxidizing conditions, dimerizes. Insome embodiments, the dimer is a homodimer. In other embodiments, thedimer is a heterodimer.

In certain embodiments, a peptide dimer inhibitor of the presentinvention is a peptide dimer comprising two peptide inhibitors of theinvention, including but not limited to a homodimer or heterdimercomprising any of the peptide sequences shown herein, e.g., in Tables3A-3H, 4A, 4B, 5A-5C, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

Certain amino acid sequences listed in Tables 3A-3H, 4A, 4B, 5A-5C, 6,7, 8, 9, 10, 11, 12, 13, 14 or 15 are shown using one letter codes foramino acids. Where only the monomer peptide inhibitor sequences areshown; however it is understood that, in certain embodiments, thesemonomer peptide inhibitors, i.e., monomer subunits, are dimerized toform peptide dimer inhibitors, in accordance with the present teachingand as shown generally, e.g., in Tables 3A-3H, 4A, 4B, 5A-5C, 6, 7, 8,9, 10, 11, 12, 13, 14 or 15.

In certain embodiments, monomer subunits of the present invention may bedimerized by a suitable linking moiety, e.g., a disulphide bridgebetween two cysteine residues, one in each peptide monomer subunit, orby another suitable linker moiety, including but not limited to thosedefined herein. Some of the monomer subunits are shown having C- andN-termini that both comprise free amine. Thus, to produce a peptidedimer inhibitor, the monomer subunit may be modified to eliminate eitherthe C- or N-terminal free amine, thereby permitting dimerization at theremaining free amine. Further, in some instances, a terminal end of oneor more monomer subunits is acylated with an acylating organic compoundselected from the group consisting of: Trifluoropentyl, Acetyl, Octonyl,Butyl, Pentyl, Hexyl, Palmityl, Trifluoromethyl butyric, cyclopentanecarboxylic, cyclopropylacetic, 4-fluorobenzoic, 4-fluorophenyl acetic,3-Phenylpropionic, tetrahedro-2H-pyran-4carboxylic, succinic acid, andglutaric acid. In some instances, monomer subunits comprise both a freecarboxy terminal and a free amino terminal, whereby a user mayselectively modify the subunit to achieve dimerization at a desiredterminus. One having skill in the art therefore, will appreciate thatthe monomer subunits of the instant invention may be selectivelymodified to achieve a single, specific amine for a desired dimerization.

It is further understood that the C-terminal residues of the monomersubunits disclosed herein are amides, unless otherwise indicated.Further, it is understood that, in certain embodiments, dimerization atthe C-terminus is facilitated by using a suitable amino acid with a sidechain having amine functionality, as is generally understood in the art.Regarding the N-terminal residues, it is generally understood thatdimerization may be achieved through the free amine of the terminalresidue, or may be achieved by using a suitable amino acid side chainhaving a free amine, as is generally understood in the art.

The linker moieties connecting monomer subunits may include anystructure, length, and/or size that is compatible with the teachingsherein. In at least one embodiment, a linker moiety is selected from thenon-limiting group consisting of cysteine, lysine, DIG, PEG4,PEG4-biotin, PEG13, PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, IDA,ADA, Boc-IDA, Glutaric acid, Isophthalic acid, 1,3-phenylenediaceticacid, 1,4-phenylenediacetic acid, 1,2-phenylenediacetic acid, Triazine,Boc-Triazine, IDA-biotin, PEG4-Biotin, AADA, suitable aliphatics,aromatics, heteroaromatics, and polyethylene glycol based linkers havinga molecular weight from approximately 400 Da to approximately 40,000 Da.Non-limiting examples of suitable linker moieties are provided in Table2A.

TABLE 2A Illustrative Linker Moieties Abbrivation Discription StructureDIG DIGlycolic acid,

PEG4 Bifunctional PEG linker with 4 PolyEthylene Glycol units

PEG13 Bifunctional PEG linker with 13 PolyEthylene Glycol units

PEG25 Bifunctional PEG linker with 25 PolyEthylene Glycol units

PEG1K Bifunctional PEG linker with PolyEthylene Glycol Mol wt of 1000 DaPEG2K Bifunctional PEG linker with PolyEthylene Glycol Mol wt of 2000 DaPEG3.4K Bifunctional PEG linker with PolyEthylene Glycol Mol wt of 3400Da PEG5K Bifunctional PEG linker with PolyEthylene Glycol Mol wt of 5000Da DIG DIGlycolic acid

β-Ala-IDA β-Ala-Iminodiacetic acid

Boc-β-Ala-IDA Boc-β-Ala- Iminodiacetic acid

Ac-β-Ala-IDA Ac-β-Ala- Iminodiacetic acid

IDA-β-Ala-Palm Palmityl-β-Ala- Iminodiacetic acid

GTA Glutaric acid

PMA Pemilic acid

AZA Azelaic acid

DDA Dodecanedioic acid

IPA Isopthalic aicd

1,3-PDA 1,3-Phenylenediacetic acid

1,4-PDA 1,4-Phenylenediacetic acid

1,2-PDA 1,2-Phenylenediacetic acid

Triazine Amino propyl Triazine di-acid

Boc-Triazine Boc-Triazine di-acid

ADA Amino diacetic acid (which may also referred to as Iminodiaceticacid)

AADA n-Acetyl amino acetic acid (which may also referred to as N-acetylIminodiacetic acid)

PEG4-Biotin PEG4-Biotin (Product number 10199, QuantaBioDesign)

IDA-Biotin N-Biotin-β-Ala- Iminodiacetic acid

Lys Lysine

In some embodiments, a peptide dimer inhibitor is dimerized via a linkermoiety. In some embodiments, a peptide dimer inhibitor is dimerized viaan intermolecular disulfide bond formed between two cysteine residues,one in each monomer subunit. In some embodiments, a peptide dimerinhibitor is dimerized via both a linker moiety and an intermoleculardisulfide bond formed between two cysteine residues. In someembodiments, the intramolecular bond is a thioether, lactam, triazole,selenoether, diselenide or olefin, instead of the disulfide bond.

An illustrative diagram of one embodiments of a dimer is shown below:

One having skill in the art will appreciate that the linker (e.g., C-and N-terminal linker) moieties disclosed herein are non-limitingexamples of suitable, and that the present invention may include anysuitable linker moiety. Thus, some embodiments of the present inventioncomprises a homo- or heterodimer peptide inhibitor comprised of twomonomer subunits selected from the peptides shown in any of Tables3A-3H, 4A, 4B, 5A-5C, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 or comprisingor consisting of a sequence presented in any of Tables 3A-3H, 4A, 4B,5A-5C, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, wherein the C- or N-terminiof the respective monomer subunits (or internal amino acid residues) arelinked by any suitable linker moiety to provide a dimer peptideinhibitor having IL-23R inhibitory activity. In certain embodiments, alinker binds to the N- or C-terminus of one monomer subunit and aninternal amino acid residue of the other monomer subunit making up thedimer. In certain embodiments, a linker binds to an internal amino acidresidue of one monomer subunit and an internal amino acid residue of theother monomer subunit making up the dimer. In further embodiments, alinker binds to the N- or C-terminus of both subunits.

In particular embodiments, a peptide inhibitor of the present inventioncomprise two or more polypeptide sequences of monomer peptide inhibitorsdescribed herein.

In one embodiment, a peptide dimer inhibitor of the present inventioncomprises two peptide monomer subunits connected via one or more linkermoieties, wherein each peptide monomer subunit comprises or consists of7 to 35 amino acid residues, 8 to 35 amino acid residues, 9 to 35 aminoacid residues, 10 to 35 amino acid residues, 7 to 25 amino acidresidues, 8 to 25 amino acid residues, 9 to 25 amino acid residues, 10to 25 amino acid residues, 7 to 20 amino acid residues, 8 to 20 aminoacid residues, 9 to 20 amino acid residues, 7 to 18 amino acid residues,8 to 18 amino acid residues, 9 to 18 amino acid residues, or 10 to 18amino acid residues and comprises the sequence of Formula Ia, asdescribed herein.

In particular embodiments, one or both of the monomer subunits comprisethe sequence of any one of Formula Ix, Ia, Ib, Ic, Id, Ie, If, Ig, Ih,Ii, Ij, Ik, Il, Im, In, Io, Ip, Iq, Iq′, Ir, Is or It, II, III, or IV asdescribed herein.

In certain embodiments, a peptide dimer inhibitor comprises two peptidemonomer subunits connected via one or more linker moieties, wherein eachpeptide monomer subunit is 8-20 amino acids in length and comprises asequence of any one of Formula Ia, Formula Ib, Formula Ic, Formula Id,Formula Ie, Formula If, Formula Ig, Formula Ih, Formula Ii, Formula Ij,Formula Ik, Formula Ti, Formula Im, Formula In, Formula Io, Formula Ip,Formula Iq, Formula Iq′, Formula Ir, Formula Is, Formula It, any of thevarious Formula II, Formula III, or Formula IV. In certain embodiments,a peptide dimer inhibitor comprises two peptide monomer subunitsconnected via one or more linker moieties, wherein each peptide monomersubunit is 8-20 amino acids in length and comprises a sequence of anyone of Formulas Ix, Ia-It, II, III, or IV.

In certain embodiments, a peptide dimer inhibitor has the structure ofFormula V:

(R¹—X—R²)₂-L  (V)

or a pharmaceutically acceptable salt or solvate thereof,

wherein each R¹ is independently absent, a bond (e.g., a covalent bond),or selected from hydrogen, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12 arylC1-C6 alkyl, a C1-C20 alkanoyl, and including PEGylated versions aloneor as spacers of any of the foregoing;

each R² is independently absent, a bond (e.g., a covalent bond), orselected from OH or NH₂;

L is a linker moiety; and

each X is an independently selected peptide monomer subunit comprisingor consisting of 7 to 35 amino acid residues, 8 to 35 amino acidresidues, 9 to 35 amino acid residues, 10 to 35 amino acid residues, 7to 25 amino acid residues, 8 to 25 amino acid residues, 9 to 25 aminoacid residues, 10 to 25 amino acid residues, 7 to 20 amino acidresidues, 8 to 20 amino acid residues, 9 to 20 amino acid residues, 7 to18 amino acid residues, 8 to 18 amino acid residues, 9 to 18 amino acidresidues, or 10 to 18 amino acid residues amino acids in length, eachcomprising or consisting of the sequence of Formula Ia, as describedherein. In particular embodiments, each peptide monomer subunitcomprises or consists of a sequence of Formula Ix, Ia, Ib, Ic, Id, Ie,If, Ig, Ih, Ii, Ij, Ik, Il, Im, In, Io, Ip, Iq, Iq′, Is, It, IIa, IIb,IIc, IId, IIIa, IIIb, Inc, IIId, Me, IVa or IVb as described herein.

In certain embodiments, one or both peptide monomer subunit of a peptidedimer inhibitor is cyclized, e.g., via an intramolecular bond between X4and X9. In certain embodiments wherein both peptide monomer subunits arecyclized, the intramolecular bond may be the same or different betweenthe two peptide monomer subinits. In certain embodiments, one or bothintramolecular bond is a disulfide bond, a thioether bond, a lactambond, a selenoether, diselenide, or an olefin bond.

In one embodiment, X4 and X9 of the one or both cyclized peptide monomersubunit is independently selected from Cys, Pen, hCys, D-Pen, D-Cys andD-hCys, and the intramolecular bond is a disulfide bond.

In one embodiment, X4 and X9 of the one or both cyclized peptide monomersubunit is independently selected from Glu, Asp, Lys, Orn, Dap, Dab,D-Dap, D-Dab, D-Asp, D-Glu and D-Lys, and the intramolecular bond is alactam bond.

In one embodiment, X4 and X9 of the one or both cyclized peptide monomersubunit are each independently selected from β-azido-Ala-OH,propargylglycine, and the peptide dimer inhibitor is cyclized through atriazole ring. In one embodiment, X4 and X9 of the one or both cyclizedpeptide monomer subunit are each independently selected from2-allylglycine, 2-(3′-butenyl)glycine, 2-(4′-pentenyl)glycine,2-(5′-hexenyl)glycine, and the peptide dimer inhibitor is cyclized vi aring closing methasis to give the corresponding olefins/‘stapledpeptides’.

In one embodiment, X4 of one or both cyclized peptide monomer subunit is2-chloromethylbenzoic acid, mercapto-propanoic acid, mercapto-butyricacid, 2-chloro-acetic acid, 3-choro-propanoic acid, 4-chloro-butyricacid, 3-chloro-isobutyric acid, or hSer(Cl), X9 of one or both cyclizedpeptide monomer subunit is hSer(Cl), Cys, Pen, hCys, D-Pen, D-Cys orD-hCys, and the intramolecular bond is a thioether bond.

In one embodiment, X4 of one or both cyclized peptide monomer subunit is2-chloromethylbenzoic acid, 2-chloro-acetic acid, 3-choro-propanoicacid, 4-chloro-butyric acid, 3-chloro-isobutyric acid, hSer(Cl), or Sec,X9 of one or both cyclized peptide monomer subunit is hSer(Cl) or Sec,and the intramolecular bond is a selenoether bond.

In certain embodiments, one or both intramolecular bond is a diselenidebond.

In certain embodiments, one or both peptide monomer subunits is linearor not cyclized.

In particular embodiments, of the peptide dimer inhibitors, each X7 andeach X11 are both W. In certain embodiments, each X7 and each X11 areboth W, each X10 is Y, and each X4 and X9 are both C. In certainembodiments, each X7 and each X11 are both W, each X10 is Y, and each X4and X9 are amino acids capable of forming an intramolecular bond that isa thioether bond, a lactam bond, a triazole, a selenoether, a diselenidebond, or an olefin bond.

In certain embodiments of the peptide dimer inhibitors, one or bothpeptide monomer subunit has a structure shown herein, e.g., in Tables3A-3I, or comprises an amino acid sequence shown herein, e.g., as setforth in Tables 3A-3I, or wherein the peptide dimer inhibitor has astructure shown herein, e.g., in Table 3F, or comprises an amino acidsequence shown herein, e.g., as set forth in Table 3F.

In particular embodiments, each R¹ is independently a bond (e.g., acovalent bond), or selected from hydrogen, a C1-C6 alkyl, a C6-C12 aryl,a C6-C12 aryl C1-C6 alkyl, a C1-C20 alkanoyl, and including PEGylatedversions alone or as spacers of any of the foregoing.

In certain embodiments of any of the peptide inhibitors having any ofthe various Formulae set forth herein, each R¹ is selected from methyl,acetyl, formyl, benzoyl, trifluoroacetyl, isovaleryl, isobutyryl,octanyl, and the conjugated amides of lauric acid, hexadecanoic acid,and γ-Glu-hexadecanoic acid.

In particular embodiments, each R² is independently a bond (e.g., acovalent bond), or selected from OH or NH₂.

In particular embodiments of any of the peptide inhibitors having any ofthe various Formulae set forth herein, each X comprises or consists of 7to 35 amino acid residues, 8 to 35 amino acid residues, 9 to 35 aminoacid residues, 10 to 35 amino acid residues, 7 to 25 amino acidresidues, 8 to 25 amino acid residues, 9 to 25 amino acid residues, 10to 25 amino acid residues, 7 to 18 amino acid residues, 8 to 18 aminoacid residues, 9 to 18 amino acid residues, or 10 to 18 amino acidresidues.

In particular embodiments, one or both X comprises or consists of thesequence of any one of Formula Ix, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii,Ij, Ik, Il, Im, In, Io, Ip, Iq, Iq′, Ir, Is, It, IIa, IIb, IIc, IId,IIIa, IIIb, IIIc, IIId, Me, Iva or IVb as described herein. In certainembodiments of any of the peptide inhibitors, including dimers, orFormulae set forth herein, an X does not comprise or consist of an aminoacid sequence set forth in US Patent Application Publication No.US2013/0029907. In certain embodiments of any of the peptide inhibitors,including dimers, or Formulae set forth herein, an X does not compriseor consist of an amino acid sequence set forth in US Patent ApplicationPublication No. US2013/0172272.

In particular embodiments of peptide inhibitors of the present invention(both monomers and dimers) comprising Cys at position X4 and Cys atposition X9, the Cys at position X4 and and the Cys at position X9 arelinked by a disulphide bridge.

In particular embodiments of peptide inhibitors of the presentinvention, each X7 and each X11 are not both W.

In particular embodiments of peptide inhibitors of the presentinvention, each X7 and each X11 are both W.

In particular embodiments of peptide inhibitors of the presentinvention, each X7 and each X11 are both W, X10 is Y, and X4 and X9 areboth C.

In certain embodiments, at least two cysteine residues of the peptidedimer inhibitor are linked by a disulphide bridge, either intramolecularor intermolecular.

In particular embodiments of either or both monomer subunit (e.g., Ix,Ia-It where permissible) present in a peptide dimer inhibitor, X4 and X9are both Cys.

In particular embodiments of either or both monomer subunit (e.g., Ix,Ia-It where permissible) present in a peptide dimer inhibitor, X7 andX11 are both W.

In particular embodiments of either or both monomer subunit (e.g., Ia-Itwhere permissible) present in a peptide dimer inhibitor, X7 and X11 areboth W, X10 is Y, and X4 and X9 are both Cys.

In particular embodiments of either or both monomer subunit (e.g., Ia-Itwhere permissible) present in a peptide dimer inhibitor, X15 is Gly orSer.

In particular embodiments of either or both monomer subunit (e.g., Ia-Itwhere permissible) present in a peptide dimer inhibitor, X16 is AEA orAEP.

In particular embodiments of either or both monomer subunit (e.g., Ia-Itwhere permissible) present in a peptide dimer inhibitor, X10 is Tyr orPhe, or an analog of Tyr or Phe.

In particular embodiments of either or both monomer subunit (e.g., Ia-Itwhere permissible) present in a peptide dimer inhibitor, X11 is Trp.

In particular embodiments of any of the peptide dimer inhibitorsdescribed herein, either or both R¹ is hydrogen.

In particular embodiments of peptide dimer inhibitors of the presentinvention, the linker moiety (L) is any of the linkers described hereinor shown in Table 2A or 2B. In certain embodiments, L is a lysinelinker, a diethylene glycol linker, an iminodiacetic acid (IDA) linker,a β-Ala-iminodiaceticacid (β-Ala-IDA) linker, or a PEG linker.

In various embodiments of any of the peptide dimer inhibitors, each ofthe peptide monomer subunits is attached to a linker moiety via itsN-terminus, C-terminus, or an internal amino acid residue.

In certain embodiments of any of the peptide dimer inhibitors, theN-terminus of each peptide monomer subunit is connected by a linkermoiety.

In certain embodiments of any of the peptide dimer inhibitors, theC-terminus of each peptide monomer subunit is connected by a linkermoiety.

In certain embodiments of any of the peptide dimer inhibitors, eachpeptide monomer subunit is connected by a linker moiety attached to aninternal amino acid.

In certain embodiments of peptide dimer inhibitors, the linker moiety isa diethylene glycol linker, an iminodiacetic acid (IDA) linker, aβ-Ala-iminodiaceticacid (β-Ala-IDA) linker, or a PEG linker.

In certain embodiments of the peptide dimer inhibitors, one or bothpeptide monomer subunit has a structure shown in Tables 3A-3H, 4A, 4B,5A-5C, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 or comprises an amino acidsequence set forth in Tables 3A-3H, 4A, 4B, 5A-5C, 6, 7, 8, 9, 10, 11,12, 13, 14 or 15.

In certain embodiments of any of the peptide inhibitors, includingdimers, or Formulae set forth herein, an X does not comprise or consistof an amino acid sequence set forth in US Patent Application PublicationNo. US2013/0029907. In certain embodiments of any of the peptideinhibitors, including dimers, or Formulas set forth herein, an X doesnot comprise or consist of an amino acid sequence set forth in US PatentApplication Publication No. US2013/0172272.

In particular embodiments of peptide inhibitors of the presentinvention, each X7 and each X11 are both W, X10 is Y, and X4 and X9 areboth Pen.

In certain embodiments, at least two cysteine residues of the peptidedimer inhibitor are linked by a disulphide bridge, either intramolecularor intermolecular.

Peptide Inhibitor Conjugates and Biopolymers

In certain embodiments, peptide inhibitors of the present invention,including both monomers and dimers, comprise one or more conjugatedchemical substituents, such as lipophilic substituents and polymericmoieties. Without wishing to be bound by any particular theory, it isbelieved that the lipophilic substituent binds to albumin in thebloodstream, thereby shielding the peptide inhibitor from enzymaticdegradation, and thus enhancing its half-life. In addition, it isbelieved that polymeric moieties enhance half-life and reduce clearancein the bloodstream. In certain embodiments, the half-life of a peptideinhibitor of the invention that includes a conjugated chemicalsubstituent is at least 100%, at least 120%, at least 150%, at least200%, at least 250%, at least 300%, at least 400%, or at least 500% ofthe half-life of the same peptide inhibitor but without the conjugatedchemical substituent. In certain embodiments, the lipophilicsubstituents and/or polypermic moieties enhance the permeability of thepeptide inhibitor through the epithelium and/or its retention in thelamina propria. In certain embodiments, the permeability through theepithelium and/or the retention in the lamina propria of a peptideinhibitor of the invention that includes a conjugated chemicalsubstituent is at 100%, at least 120%, at least 150%, at least 200%, atleast 250%, at least 300%, at least 400%, or at least 500% of thehalf-life of the same peptide inhibitor but without the conjugatedchemical substituent.

In one embodiment, a side chain of one or more amino acid residues(e.g., Lys residues) in a peptide inhibitor of the invention isconjugated (e.g., covalently attached) to a lipophilic substituent. Thelipophilic substituent may be covalently bonded to an atom in the aminoacid side chain, or alternatively may be conjugated to the amino acidside chain via one or more spacers. The spacer, when present, mayprovide spacing between the peptide analogue and the lipophilicsubstituent.

In certain embodiments, the lipophilic substituent may comprise ahydrocarbon chain having from 4 to 30 C atoms, for example at least 8 or12 C atoms, and preferably 24 C atoms or fewer, or 20 C atoms or fewer.The hydrocarbon chain may be linear or branched and may be saturated orunsaturated. In certain embodiments, the hydrocarbon chain issubstituted with a moiety which forms part of the attachment to theamino acid side chain or the spacer, for example an acyl group, asulfonyl group, an N atom, an O atom or an S atom. In some embodiments,the hydrocarbon chain is substituted with an acyl group, and accordinglythe hydrocarbon chain may form part of an alkanoyl group, for examplepalmitoyl, caproyl, lauroyl, myristoyl or stearoyl.

A lipophilic substituent may be conjugated to any amino acid side chainin a peptide inhibitor of the invention. In certain embodiment, theamino acid side chain includes a carboxy, hydroxyl, thiol, amide oramine group, for forming an ester, a sulphonyl ester, a thioester, anamide or a sulphonamide with the spacer or lipophilic substituent. Forexample, the lipophilic substituent may be conjugated to Asn, Asp, Glu,Gln, His, Lys, Arg, Ser, Thr, Tyr, Trp, Cys or Dbu, Dpr or Orn. Incertain embodiments, the lipophilic substituent is conjugated to Lys. Anamino acid shown as Lys in any of the formula provided herein may bereplaced by, e.g., Dbu, Dpr or Orn where a lipophilic substituent isadded.

In certain embodiments, the peptide inhibitors of the present inventionmay be modified, e.g., to enhance stability, increase permeability, orenhance drug like characteristics, through conjugation of a chemicalmoiety to one or more amino acid side chain within the peptide. Forexample, the N(epsilon) of lysine N(epsilon), the β-carboxyl ofaspartic, or the γ-carboxyl of glutamic acid may be appropriatelyfunctionalized. Thus, to produce the modified peptide, an amino acidwithin the peptide may be appropriately modified. Further, in someinstances, the side chain is acylated with an acylating organic compoundselected from the group consisting of: Trifluoropentyl, Acetyl, Octonyl,Butyl, Pentyl, Hexyl, Palmityl, Trifluoromethyl butyric, cyclopentanecarboxylic, cyclopropylacetic, 4-fluorobenzoic, 4-fluorophenyl acetic,3-Phenylpropionic, tetrahedro-2H-pyran-4carboxylic, succinic acidglutaric acid or bile acids. One having skill is the art will appreciatethat a series of conjugates can be linked, e.g., for example PEG4,isoglu and combinations thereof. One having skill is the art willappreciate that an amino acid with the peptide can be isostericallyreplaced, for example, Lys may be replaced for Dap, Dab, α-MeLys orOrn.Examples of modified residues within a peptide are shown in Table 1B.

TABLE 1B Examples of modified Lysine, Asp and Asn within the peptide

In further embodiments of the present invention, alternatively oradditionally, a side-chain of one or more amino acid residues in apeptide inhibitor of the invention is conjugated to a polymeric moiety,for example, in order to increase solubility and/or half-life in vivo(e.g. in plasma) and/or bioavailability. Such modifications are alsoknown to reduce clearance (e.g. renal clearance) of therapeutic proteinsand peptides.

As used herein, “Polyethylene glycol” or “PEG” is a polyether compoundof general formula H—(O-CH2-CH2)n-OH. PEGs are also known aspolyethylene oxides (PEOs) or polyoxyethylenes (POEs), depending ontheir molecular weight PEO, PEE, or POG, as used herein, refers to anoligomer or polymer of ethylene oxide. The three names are chemicallysynonymous, but PEG has tended to refer to oligomers and polymers with amolecular mass below 20,000 Da, PEO to polymers with a molecular massabove 20,000 Da, and POE to a polymer of any molecular mass. PEG and PEOare liquids or low-melting solids, depending on their molecular weights.Throughout this disclosure, the 3 names are used indistinguishably. PEGsare prepared by polymerization of ethylene oxide and are commerciallyavailable over a wide range of molecular weights from 300 Da to10,000,000 Da. While PEG and PEO with different molecular weights finduse in different applications, and have different physical properties(e.g. viscosity) due to chain length effects, their chemical propertiesare nearly identical. The polymeric moiety is preferably water-soluble(amphiphilic or hydrophilic), non-toxic, and pharmaceutically inert.Suitable polymeric moieties include polyethylene glycols (PEG), homo- orco-polymers of PEG, a monomethyl-substituted polymer of PEG (mPEG), orpolyoxyethylene glycerol (POG). See, for example, Int. J. Hematology68:1 (1998); Bioconjugate Chem. 6:150 (1995); and Crit. Rev. Therap.Drug Carrier Sys. 9:249 (1992). Also encompassed are PEGs that areprepared for purpose of half life extension, for example,mono-activated, alkoxy-terminated polyalkylene oxides (POA's) such asmono-methoxy-terminated polyethyelene glycols (mPEG's); bis activatedpolyethylene oxides (glycols) or other PEG derivatives are alsocontemplated. Suitable polymers will vary substantially by weightsranging from about 200 Da to about 40,000 Da or from about 200 Da toabout 60,000 Da are usually selected for the purposes of the presentinvention. In certain embodiments, PEGs having molecular weights from200 to 2,000 or from 200 to 500 are used. Different forms of PEG mayalso be used, depending on the initiator used for the polymerizationprocess—a common common initiator is a monofunctional methyl ether PEG,or methoxypoly(ethylene glycol), abbreviated mPEG.

Lower-molecular-weight PEGs are also available as pure oligomers,referred to as monodisperse, uniform, or discrete. These are used incertain embodiments of the present invention.

PEGs are also available with different geometries: branched PEGs havethree to ten PEG chains emanating from a central core group; star PEGshave 10 to 100 PEG chains emanating from a central core group; and combPEGs have multiple PEG chains normally grafted onto a polymer backbone.PEGs can also be linear. The numbers that are often included in thenames of PEGs indicate their average molecular weights (e.g. a PEG withn=9 would have an average molecular weight of approximately 400 daltons,and would be labeled PEG 400.

As used herein, “PEGylation” is the act of covalently coupling a PEGstructure to the peptide inhibitor of the invention, which is thenreferred to as a “PEGylated peptide inhibitor”. In certain embodiments,the PEG of the PEGylated side chain is a PEG with a molecular weightfrom about 200 to about 40,000. In some embodiments, a spacer of apeptide of formula I, formula I′, or formula I″ is PEGylated. In certainembodiments, the PEG of a PEGylated spacer is PEG3, PEG4, PEG5, PEG6,PEG7, PEG8, PEG9, PEG10, or PEG11. In certain embodiments, the PEG of aPEGylated spacer is PEG3 or PEG8.

Other suitable polymeric moieties include poly-amino acids such aspoly-lysine, poly-aspartic acid and poly-glutamic acid (see for exampleGombotz, et al. (1995), Bioconjugate Chem., vol. 6: 332-351; Hudecz, etal. (1992), Bioconjugate Chem., vol. 3, 49-57 and Tsukada, et al.(1984), J. Natl. Cancer Inst., vol. 73, 721-729. The polymeric moietymay be straight-chain or branched. In some embodiments, it has amolecular weight of 500-40,000 Da, for example 500-10,000 Da, 1000-5000Da, 10,000-20,000 Da, or 20,000-40,000 Da.

In some embodiments, a peptide inhibitor of the invention may comprisetwo or more such polymeric moieties, in which case the total molecularweight of all such moieties will generally fall within the rangesprovided above.

In some embodiments, the polymeric moiety is coupled (by covalentlinkage) to an amino, carboxyl or thiol group of an amino acid sidechain. Certain examples are the thiol group of Cys residues and theepsilon amino group of Lys residues, and the carboxyl groups of Asp andGlu residues may also be involved.

The skilled worker will be well aware of suitable techniques which canbe used to perform the coupling reaction. For example, a PEG moietybearing a methoxy group can be coupled to a Cys thiol group by amaleimido linkage using reagents commercially available from NektarTherapeutics AL. See also WO 2008/101017, and the references citedabove, for details of suitable chemistry. A maleimide-functionalised PEGmay also be conjugated to the side-chain sulfhydryl group of a Cysresidue.

As used herein, disulfide bond oxidation can occur within a single stepor is a two step process. As used herein, for a single oxidation step,the trityl protecting group is often employed during assembly, allowingdeprotection during cleavage, followed by solution oxidation. When asecond disulfide bond is required, one has the option of native orselective oxidation. For selective oxidation requiring orthogonalprotecting groups, Acm and Trityl is used as the protecting groups forcysteine. Cleavage results in the removal of one protecting pair ofcysteine allowing oxidation of this pair. The second oxidativedeprotection step of the cysteine protected Acm group is then performed.For native oxidation, the trityl protecting group is used for allcysteines, allowing for natural folding of the peptide. A skilled workerwill be well aware of suitable techniques which can be used to performthe oxidation step.

Several chemical moieties, including poly(ethylene)glycol, react withfunctional groups present in the twenty naturally occurring amino acids,such as, for example, the epsilon amino group in lysine amino acidresidues, the thiol present in cysteine amino acid residues, or othernucleophilic amino acid side chains. When multiple naturally occurringamino acids react in a peptide inhibitor, these non-specific chemicalreactions result in a final peptide inhibitor that contains many isomersof peptides conjugated to one or more poly(ethylene)glycol strands atdifferent locations within the peptide inhibitor.

One advantage of certain embodiments of the present invention includesthe ability to add one or more chemical moiety (such as PEG) byincorporating one or more non-natural amino acid(s) that possess uniquefunctional groups that react with an activated PEG by way of chemistrythat is unreactive with the naturally occurring amino acids present inthe peptide inhibitor. For example, azide and alkyne groups areunreactive with all naturally occurring functional groups in a protein.Thus, a non-natural amino acid may be incorporated in one or morespecific sites in a peptide inhibitor where PEG or another modificationis desired without the undesirable non-specific reactions. In certainembodiments, the particular chemistry involved in the reaction resultsin a stable, covalent link between the PEG strand and the peptideinhibitor. In addition, such reactions may be performed in mild aqueousconditions that are not damaging to most peptides. In certainembodiments, the non-natural amino acid residue is AHA.

Chemical moieties attached to natural amino acids are limited in numberand scope. By contrast, chemical moieties attached to non-natural aminoacids can utilize a significantly greater spectrum of useful chemistriesby which to attach the chemical moiety to the target molecule.Essentially any target molecule, including any protein (or portionthereof) that includes a non-natural amino acid, e.g., a non-naturalamino acid containing a reactive site or side chain where a chemicalmoiety may attach, such as an aldehyde- or keto-derivatized amino acid,can serve as a substrate for attaching a chemical moiety.

Numerous chemical moieties may be joined or linked to a particularmolecule through various known methods in the art. A variety of suchmethods are described in U.S. Pat. No. 8,568,706. As an illustrativeexample, azide moieties may be useful in conjugating chemical moietiessuch as PEG or others described herein. The azide moiety serves as areactive functional group, and is absent in most naturally occurringcompounds (thus it is unreactive with the native amino acids ofnaturally occurring compounds). Azides also undergo a selective ligationwith a limited number of reaction partners, and azides are small and canbe introduced to biological samples without altering the molecular sizeof significantly. One reaction that allows incorporation or introductionof azides to molecules is the copper-mediated Huisgen [3+2]cycloaddition of an azide. This reaction can be used for the selectivePEGylation of peptide inhibitors. (Tornoe et al., J. Org. Chem. 67:3057, 2002; Rostovtsev et al., Angew. Chem., Int. Ed. 41: 596, 2002; andWang et al., J. Am. Chem. Soc. 125: 3192, 2003, Speers et al., J. Am.Chem. Soc., 2003, 125, 4686).

Illustrative Peptide Inhibitors and Peptide Dimer Inhibitors, andMethods of Making the Same

The present invention thus provides various peptide inhibitors whichbind or associate with IL-23, to disrupt or block binding between IL-23and IL-23R.

Illustrative peptide inhibitors and peptide dimer inhibitors of thepresent invention are shown in Tables 3A-3H, 4A, 4B, 5A-5C, 6, 7, 8, 9,10, 11, 12, 13, 14 or 15 provides the amino acid sequence of selectedmonomer peptide inhibitors and peptide dimer inhibitors, and indicatesthe linker moiety present in the peptide dimer inhibitors. According tothe protocols discussed herein, a number of the peptide inhibitors andpeptide dimer inhibitors shown in Tables 3A-3H, 4A, 4B, 5A-5C, 6, 7, 8,9, 10, 11, 12, 13, 14 or 15 were synthesized. Tables 3A-3H, 4A, 4B,5A-5C, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 provide the IC50 values forselected monomer peptide inhibitors and peptide dimer inhibitors ininhibiting IL-23 binding to the IL-23R, or in inhibiting IL-23 signalingas determined by measuring changes in phospho-STAT3 levels, as describedin the accompanying Examples.

The peptide inhibitors of the present invention may be synthesized bymany techniques that are known to those skilled in the art. In certainembodiments, monomer subunits are synthesized, purified, and dimerizedusing the techniques described in the accompanying Examples. In certainembodiments, the present invention provides a method of producing apeptide inhibitor (or monomer subunit thereof) of the present invention,comprising chemically synthesizing a peptide comprising, consisting of,or consisting essentially of a peptide having an amino acid sequencedescribed herein, including but not limited to any of the amino acidsequences set forth in any of Formulas I, II, III, IV, V or VI or Tables3A-3H, 4A, 4B, 5A-5C, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. In otherembodiments, the peptide is recombinantly synthesized, instead of beingchemically synthesized. In certain embodiments, the peptide inhibitor isa dimer, and the method comprises synthezing both monomer subunits ofthe peptide dimer inhibitor and then dimerizing the two monomer subunitsto produce the peptide dimer inhibitor. In various embodiments,dimerization is accomplished via any of the various methods describedherein. In particular embodiments, methods of producing a peptideinhibitor (or monomer subunit thereof) further comprise cyclizing thepeptide inhibitor (or monomer subunit thereof) after its synthesis. Inparticular embodiments, cyclization is accomplished via any of thevarious methods described herein. In certain embodiments, the presentinvention provides a method of producing a peptide inhibitor (or monomersubunit thereof) of the present invention, comprising introducing anintramolecular bond, e.g., a disulfide, an amide, or a thioether bondbetween two amino acids residues within a peptide comprising, consistingof, or consisting essentially of a peptide having an amino acid sequencedescribed herein, including but not limited to any of the amino acidsequences set forth in any of Formulas I, II, III, IV, V or VI or Tables3A-3H, 4A, 4B, 5A-5C, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

In related embodiments, the present invention includes polynucleotidesthat encode a polypeptide having a sequence set forth in any one ofFormulas I, II, III, IV, V or VI or Tables 3A-3H, 4A, 4B, 5A-5C, 6, 7,8, 9, 10, 11, 12, 13, 14 or 15.

In addition, the present invention includes vectors, e.g., expressionvectors, comprising a polynucleotide of the present invention.

Methods of Treatment

In certain embodiments, the present invention includes methods ofinhibiting IL-23 binding to an IL-23R on a cell, comprising contactingthe IL-23 with a peptide inhibitor of the present invention. In certainembodiments, the cell is a mammalian cell. In particular embodiments,the method is performed in vitro or in vivo. Inhibition of binding maybe determined by a variety of routine experimental methods and assaysknown in the art.

In certain embodiments, the present invention includes methods ofinhibiting IL-23 signaling by a cell, comprising contacting the IL-23with a peptide inhibitor of the present invention. In certainembodiments, the cell is a mammalian cell. In particular embodiments,the method is performed in vitro or in vivo. In particular embodiments,the inhibition of IL-23 signalling may be determined by measuringchanges in phospho-STAT3 levels in the cell.

In some embodiments, the present invention provides methods for treatinga subject afflicted with a condition or indication associated with IL-21or IL-23R (e.g., activation of the IL-23/IL-23R signaling pathway),wherein the method comprises administering to the subject a peptideinhibitor of the present invention. In one embodiment, a method isprovided for treating a subject afflicted with a condition or indicationcharacterized by inappropriate, deregulated, or increased IL-23 orIL-23R activity or signaling, comprising administering to the individuala peptide inhibitor of the present invention in an amount sufficient toinhibit (partially or fully) binding of IL-23 to IL-23R in the subject.In particular embodiments, the inhibition of IL-23 binding to IL-23Roccurs in particular organs or tissues of the subject, e.g., thestomach, small intestine, large intestine/colon, intestinal mucosa,lamina propria, Peyer's Patches, mesenteric lymph nodes, or lymphaticducts.

In some embodiments, methods of the present invention comprise providinga peptide inhibitor of the present invention to a subject in needthereof. In particular embodiments, the subject in need thereof has beendiagnosed with or has been determined to be at risk of developing adisease or disorder associated with IL-23/IL-23R. In particularembodiments, the subject is a mammal.

In certain embodiments, the disease or disorder is autoimmuneinflammation and related diseases and disorders, such as multiplesclerosis, asthma, rheumatoid arthritis, inflammatory bowel diseases(IBDs), juvenile IBD, adolescent IBD, Crohn's disease, sarcoidosis,Systemic Lupus Erythematosus, ankylosing spondylitis (axialspondyloarthritis), psoriatic arthritis, or psoriasis. In particularembodiments, the disease or disorder is psoriasis (e.g., plaquepsoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis,Palmo-Plantar Pustulosis, psoriasis vulgaris, or erythrodermicpsoriasis), atopic dermatitis, acne ectopica, ulcerative colitis,Crohn's disease, Celiac disease (nontropical Sprue), enteropathyassociated with seronegative arthropathies, microscopic colitis,collagenous colitis, eosinophilic gastroenteritis/esophagitis, colitisassociated with radio- or chemo-therapy, colitis associated withdisorders of innate immunity as in leukocyte adhesion deficiency-1,chronic granulomatous disease, glycogen storage disease type 1b,Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-AldrichSyndrome, pouchitis resulting after proctocolectomy and ileoanalanastomosis, gastrointestinal cancer, pancreatitis, insulin-dependentdiabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliarycirrhosis, viral-associated enteropathy, pericholangitis, chronicbronchitis, chronic sinusitis, asthma, uveitis, or graft versus hostdisease.

In certain related embodiments, the present invention provides a methodof selectively inhibiting IL-23 or IL-23R signaling (or the binding ofIL-23 to IL-23R) in a subject in need thereof, comprising providing tothe subject a peptide inhibitor of the present invention. In particularembodiments, the present invention includes a method of selectivelyinhibiting IL-23 or IL-23R signaling (or the binding of IL-23 to IL-23R)in the GI tract of a subject in need thereof, comprising providing tothe subject a peptide inhibitor of the present invention by oraladministration. In particular embodiments, exposure of the administeredpeptide inhibitor in GI tissues (e.g., small intestine or colon) is atleast 10-fold, at least 20-fold, at least 50-fold, or at least 100-foldgreater than the exposure in the blood. In particular embodiments, thepresent invention includes a method of selectively inhibiting IL23 orIL23R signaling (or the binding of IL23 to IL23R) in the GI tract of asubject in need thereof, comprising providing to the subject a peptideinhibitor, wherein the peptide inhibitor does not block the interactionbetween IL-6 and IL-6R or antagonize the IL-12 signaling pathway. In afurther related embodiment, the present invention includes a method ofinhibiting GI inflammation and/or neutrophil infiltration to the GI,comprising providing to a subject in need thereof a peptide inhibitor ofthe present invention. In some embodiments, methods of the presentinvention comprise providing a peptide inhibitor of the presentinvention (i.e., a first therapeutic agent) to a subject in need thereofin combination with a second therapeutic agent. In certain embodiments,the second therapeutic agent is provided to the subject before and/orsimultaneously with and/or after the peptide inhibitor is administeredto the subject. In particular embodiments, the second therapeutic agentis an anti-inflammatory agent. In certain embodiments, the secondtherapeutic agent is a non-steroidal anti-inflammatory drug, steroid, orimmune modulating agent. In another embodiment, the method comprisesadministering to the subject a third therapeutic agent. In certainembodiments, the second therapeutic agent is an antibody that bindsIL-23 or IL-23R.

In particular embodiments, the peptide inhibitor, or the pharmaceuticalcomposition comprising a peptide inhibitor, is suspended in asustained-release matrix. A sustained-release matrix, as used herein, isa matrix made of materials, usually polymers, which are degradable byenzymatic or acid-base hydrolysis or by dissolution. Once inserted intothe body, the matrix is acted upon by enzymes and body fluids. Asustained-release matrix desirably is chosen from biocompatiblematerials such as liposomes, polylactides (polylactic acid),polyglycolide (polymer of glycolic acid), polylactide co-glycolide(copolymers of lactic acid and glycolic acid) polyanhydrides,poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitinsulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides,nucleic acids, polyamino acids, amino acids such as phenylalanine,tyrosine, isoleucine, polynucleotides, polyvinyl propylene,polyvinylpyrrolidone and silicone. One embodiment of a biodegradablematrix is a matrix of one of either polylactide, polyglycolide, orpolylactide co-glycolide (co-polymers of lactic acid and glycolic acid).

In certain embodiments, the present invention includes pharmaceuticalcompositions comprising one or more peptide inhibitors of the presentinvention and a pharmaceutically acceptable carrier, diluent orexcipient. A pharmaceutically acceptable carrier, diluent or excipientrefers to a non-toxic solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Preventionof the action of microorganisms may be ensured by the inclusion ofvarious antibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like.

In certain embodiments, the compositions are administered orally,parenterally, intracisternally, intravaginally, intraperitoneally,intrarectally, topically (as by powders, ointments, drops, suppository,or transdermal patch), by inhalation (such as intranasal spray),ocularly (such as intraocularly) or buccally. The term “parenteral” asused herein refers to modes of administration which include intravenous,intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermaland intraarticular injection and infusion. Accordingly, in certainembodiments, the compositions are formulated for delivery by any ofthese routes of administration.

In certain embodiments, pharmaceutical compositions for parenteralinjection comprise pharmaceutically acceptable sterile aqueous ornonaqueous solutions, dispersions, suspensions or emulsions, or sterilepowders, for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol, and the like), carboxymethylcellulose and suitable mixturesthereof, β-cyclodextrin, vegetable oils (such as olive oil), andinjectable organic esters such as ethyl oleate. Proper fluidity may bemaintained, for example, by the use of coating materials such aslecithin, by the maintenance of the required particle size in the caseof dispersions, and by the use of surfactants. These compositions mayalso contain adjuvants such as preservative, wetting agents, emulsifyingagents, and dispersing agents. Prolonged absorption of an injectablepharmaceutical form may be brought about by the inclusion of agentswhich delay absorption, such as aluminum monostearate and gelatin.

Injectable depot forms include those made by forming microencapsulematrices of the peptide inhibitor in one or more biodegradable polymerssuch as polylactide-polyglycolide, poly(orthoesters), poly(anhydrides),and (poly)glycols, such as PEG. Depending upon the ratio of peptide topolymer and the nature of the particular polymer employed, the rate ofrelease of the peptide inhibitor can be controlled. Depot injectableformulations are also prepared by entrapping the peptide inhibitor inliposomes or microemulsions compatible with body tissues.

The injectable formulations may be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Topical administration includes administration to the skin or mucosa,including surfaces of the lung and eye. Compositions for topical lungadministration, including those for inhalation and intranasal, mayinvolve solutions and suspensions in aqueous and non-aqueousformulations and can be prepared as a dry powder which may bepressurized or non-pressurized. In non-pressurized powder compositions,the active ingredient may be finely divided form may be used inadmixture with a larger-sized pharmaceutically acceptable inert carriercomprising particles having a size, for example, of up to 100micrometers in diameter. Suitable inert carriers include sugars such aslactose.

Alternatively, the composition may be pressurized and contain acompressed gas, such as nitrogen or a liquefied gas propellant. Theliquefied propellant medium and indeed the total composition may be suchthat the active ingredient does not dissolve therein to any substantialextent. The pressurized composition may also contain a surface activeagent, such as a liquid or solid non-ionic surface active agent or maybe a solid anionic surface active agent. It is preferred to use thesolid anionic surface active agent in the form of a sodium salt.

A further form of topical administration is to the eye. A peptideinhibitor of the invention may be delivered in a pharmaceuticallyacceptable ophthalmic vehicle, such that the peptide inhibitor ismaintained in contact with the ocular surface for a sufficient timeperiod to allow the peptide inhibitor to penetrate the corneal andinternal regions of the eye, as for example the anterior chamber,posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea,iris/ciliary, lens, choroid/retina and sclera. The pharmaceuticallyacceptable ophthalmic vehicle may, for example, be an ointment,vegetable oil or an encapsulating material. Alternatively, the peptideinhibitors of the invention may be injected directly into the vitreousand aqueous humour.

Compositions for rectal or vaginal administration include suppositorieswhich may be prepared by mixing the peptide inhibitors of this inventionwith suitable non-irritating excipients or carriers such as cocoabutter, polyethylene glycol or a suppository wax, which are solid atroom temperature but liquid at body temperature and, therefore, melt inthe rectum or vaginal cavity and release the active compound.

Peptide inhibitors of the present invention may also be administered inliposomes or other lipid-based carriers. As is known in the art,liposomes are generally derived from phospholipids or other lipidsubstances. Liposomes are formed by mono- or multi-lamellar hydratedliquid crystals that are dispersed in an aqueous medium. Any non-toxic,physiologically acceptable and metabolizable lipid capable of formingliposomes can be used. The present compositions in liposome form cancontain, in addition to a peptide inhibitor of the present invention,stabilizers, preservatives, excipients, and the like. In certainembodiments, the lipids comprise phospholipids, including thephosphatidyl cholines (lecithins) and serines, both natural andsynthetic. Methods to form liposomes are known in the art.

Pharmaceutical compositions to be used in the invention suitable forparenteral administration may comprise sterile aqueous solutions and/orsuspensions of the peptide inhibitors made isotonic with the blood ofthe recipient, generally using sodium chloride, glycerin, glucose,mannitol, sorbitol, and the like.

In some aspects, the invention provides a pharmaceutical composition fororal delivery. Compositions and peptide inhibitors of the instantinvention may be prepared for oral administration according to any ofthe methods, techniques, and/or delivery vehicles described herein.Further, one having skill in the art will appreciate that the peptideinhibitors of the instant invention may be modified or integrated into asystem or delivery vehicle that is not disclosed herein, yet is wellknown in the art and compatible for use in oral delivery of peptides.

In certain embodiments, formulations for oral administration maycomprise adjuvants (e.g. resorcinols and/or nonionic surfactants such aspolyoxyethylene oleyl ether and n-hexadecylpolyethylene ether) toartificially increase the permeability of the intestinal walls, and/orenzymatic inhibitors (e.g. pancreatic trypsin inhibitors,diisopropylfluorophosphate (DFF) or trasylol) to inhibit enzymaticdegradation. In certain embodiments, the peptide inhibitor of asolid-type dosage form for oral administration can be mixed with atleast one additive, such as sucrose, lactose, cellulose, mannitol,trehalose, raffinose, maltitol, dextran, starches, agar, alginates,chitins, chitosans, pectins, gum tragacanth, gum arabic, gelatin,collagen, casein, albumin, synthetic or semisynthetic polymer, orglyceride. These dosage forms can also contain other type(s) ofadditives, e.g., inactive diluting agent, lubricant such as magnesiumstearate, paraben, preserving agent such as sorbic acid, ascorbic acid,alpha-tocopherol, antioxidants such as cysteine, disintegrators,binders, thickeners, buffering agents, pH adjusting agents, sweeteningagents, flavoring agents or perfuming agents.

In particular embodiments, oral dosage forms or unit doses compatiblefor use with the peptide inhibitors of the present invention may includea mixture of peptide inhibitor and nondrug components or excipients, aswell as other non-reusable materials that may be considered either as aningredient or packaging. Oral compositions may include at least one of aliquid, a solid, and a semi-solid dosage forms. In some embodiments, anoral dosage form is provided comprising an effective amount of peptideinhibitor, wherein the dosage form comprises at least one of a pill, atablet, a capsule, a gel, a paste, a drink, a syrup, ointment, andsuppository. In some instances, an oral dosage form is provided that isdesigned and configured to achieve delayed release of the peptideinhibitor in the subject's small intestine and/or colon.

In one embodiment, an oral pharmaceutical composition comprising apeptide inhibitor of the present invention comprises an enteric coatingthat is designed to delay release of the peptide inhibitor in the smallintestine. In at least some embodiments, a pharmaceutical composition isprovided which comprises a peptide inhibitor of the present inventionand a protease inhibitor, such as aprotinin, in a delayed releasepharmaceutical formulation. In some instances, pharmaceuticalcompositions of the instant invention comprise an enteric coat that issoluble in gastric juice at a pH of about 5.0 or higher. In at least oneembodiment, a pharmaceutical composition is provided comprising anenteric coating comprising a polymer having dissociable carboxylicgroups, such as derivatives of cellulose, including hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate and cellulose acetatetrimellitate and similar derivatives of cellulose and other carbohydratepolymers.

In one embodiment, a pharmaceutical composition comprising a peptideinhibitor of the present invention is provided in an enteric coating,the enteric coating being designed to protect and release thepharmaceutical composition in a controlled manner within the subject'slower gastrointestinal system, and to avoid systemic side effects. Inaddition to enteric coatings, the peptide inhibitors of the instantinvention may be encapsulated, coated, engaged or otherwise associatedwithin any compatible oral drug delivery system or component. Forexample, in some embodiments a peptide inhibitor of the presentinvention is provided in a lipid carrier system comprising at least oneof polymeric hydrogels, nanoparticles, microspheres, micelles, and otherlipid systems.

To overcome peptide degradation in the small intestine, some embodimentsof the present invention comprise a hydrogel polymer carrier system inwhich a peptide inhibitor of the present invention is contained, wherebythe hydrogel polymer protects the peptide inhibitor from proteolysis inthe small intestine and/or colon. The peptide inhibitors of the presentinvention may further be formulated for compatible use with a carriersystem that is designed to increase the dissolution kinetics and enhanceintestinal absorption of the peptide. These methods include the use ofliposomes, micelles and nanoparticles to increase GI tract permeation ofpeptides.

Various bioresponsive systems may also be combined with one or morepeptide inhibitor of the present invention to provide a pharmaceuticalagent for oral delivery. In some embodiments, a peptide inhibitor of theinstant invention is used in combination with a bioresponsive system,such as hydrogels and mucoadhesive polymers with hydrogen bonding groups(e.g., PEG, poly(methacrylic) acid [PMAA], cellulose, Eudragit®,chitosan and alginate) to provide a therapeutic agent for oraladministration. Other embodiments include a method for optimizing orprolonging drug residence time for a peptide inhibitor disclosed herein,wherein the surface of the peptide inhibitor surface is modified tocomprise mucoadhesive properties through hydrogen bonds, polymers withlinked mucins or/and hydrophobic interactions. These modified peptidemolecules may demonstrate increase drug residence time within thesubject, in accordance with a desired feature of the invention.Moreover, targeted mucoadhesive systems may specifically bind toreceptors at the enterocytes and M-cell surfaces, thereby furtherincreasing the uptake of particles containing the peptide inhibitor.

Other embodiments comprise a method for oral delivery of a peptideinhibitor of the present invention, wherein the peptide inhibitor isprovided to a subject in combination with permeation enhancers thatpromote the transport of the peptides across the intestinal mucosa byincreasing paracellular or transcellular permeation. For example, in oneembodiment, a permeation enhancer is combined with a peptide inhibitor,wherein the permeation enhancer comprises at least one of a long-chainfatty acid, a bile salt, an amphiphilic surfactant, and a chelatingagent. In one embodiment, a permeation enhancer comprising sodiumN-[hydroxybenzoyl)amino] caprylate is used to form a weak noncovalentassociation with the peptide inhibitor of the instant invention, whereinthe permeation enhancer favors membrane transport and furtherdissociation once reaching the blood circulation. In another embodiment,a peptide inhibitor of the present invention is conjugated tooligoarginine, thereby increasing cellular penetration of the peptideinto various cell types. Further, in at least one embodiment anoncovalent bond is provided between a peptide inhibitor of the presentinvention and a permeation enhancer selected from the group consistingof a cyclodextrin (CD) and a dendrimers, wherein the permeation enhancerreduces peptide aggregation and increasing stability and solubility forthe peptide inhibitor molecule.

Other embodiments of the invention provide a method for treating asubject with a peptide inhibitor of the present invention having anincreased half-life. In one aspect, the present invention provides apeptide inhibitor having a half-life of at least several hours to oneday in vitro or in vivo (e.g., when administered to a human subject)sufficient for daily (q.d.) or twice daily (b.i.d.) dosing of atherapeutically effective amount. In another embodiment, the peptideinhibitor has a half-life of three days or longer sufficient for weekly(q.w.) dosing of a therapeutically effective amount. Further, in anotherembodiment, the peptide inhibitor has a half-life of eight days orlonger sufficient for bi-weekly (b.i.w.) or monthly dosing of atherapeutically effective amount. In another embodiment, the peptideinhibitor is derivatized or modified such that is has a longer half-lifeas compared to the underivatized or unmodified peptide inhibitor. Inanother embodiment, the peptide inhibitor contains one or more chemicalmodifications to increase serum half-life.

When used in at least one of the treatments or delivery systemsdescribed herein, a peptide inhibitor of the present invention may beemployed in pure form or, where such forms exist, in pharmaceuticallyacceptable salt form.

The total daily usage of the peptide inhibitors and compositions of thepresent invention can be decided by the attending physician within thescope of sound medical judgment. The specific therapeutically effectivedose level for any particular subject will depend upon a variety offactors including: a) the disorder being treated and the severity of thedisorder; b) activity of the specific compound employed; c) the specificcomposition employed, the age, body weight, general health, sex and dietof the patient; d) the time of administration, route of administration,and rate of excretion of the specific peptide inhibitor employed; e) theduration of the treatment; f) drugs used in combination or coincidentalwith the specific peptide inhibitor employed, and like factors wellknown in the medical arts.

In particular embodiments, the total daily dose of the peptideinhibitors of the invention to be administered to a human or othermammal host in single or divided doses may be in amounts, for example,from 0.0001 to 300 mg/kg body weight daily or 1 to 300 mg/kg body weightdaily.

Non-Invasive Detection of Intestinal Inflammation

The peptide inhibitors of the invention may be used for detection,assessment and diagnosis of intestinal inflammation by microPET imaging,wherein the peptide inhibitor is labeled with a chelating group or adetectable label, as part of a a non-invasive diagnostic procedure. Inone embodiment, a peptide inhibitor is conjugated with a bifunctionalchelator. In another embodiment, a peptide inhibitor is radiolabeled.The labeled peptide inhibitor is then administered to a subject orallyor rectally. In one embodiment, the labeled peptide inhibitor isincluded in drinking water. Following uptake of the peptide inhibitor,microPET imaging may be used to visualize inflammation throughout thesubject's bowels and digestive track.

Identification of Peptide Inhibitors that Inhibit IL-23 Signalling

As described herein, in certain embodiments, peptide inhibitors of thepresent invention preferentially bind to human IL-23R and/or rat IL-23Ras compared to mouse IL-23R. Mouse IL-23R contains additional aminoacids as compared to human IL-23R or rat IL-23R in the regioncorresponding to about amino acid residue 315 to about amino acidresidue 340 of the mouse IL23R protein, e.g., amino acid regionNWQPWSSPFVHQTSQETGKR (SEQ ID NO: 261) (see, e.g., FIG. 4). In particularembodiments, the peptide inhibitors bind to a region of human IL-23Rfrom about amino acid 230 to about amino acid residue 370.

The present invention provides a new method to identify an inhibitor(e.g., a peptide inhibitor) of IL-23R, based on identifying an agent(e.g., a peptide) that preferentially binds to human IL-23R or ratIL-23R as compared to mouse IL-23R. In certain embodiments, the methodcomprises: (a) determining an amount of binding of a candidate agent toa human IL-23R polypeptide or a rat IL-23R polypeptide; (b) determiningan amount of binding of the candidate agent to the mouse IL-23Rpolypeptide; and (c) comparing the determined amount of binding to thehuman IL-23R polypeptide or the rat IL-23R polypeptide to the determinedamount of binding to the mouse IL-23R polypeptide, wherein if thedetermined amount of binding to the human IL-23R polypeptide or the ratIL-23R polypeptide is greater than the amount of binding to the mouseIL-23R polypeptide, the candidate compound is an inhibitor of IL-23R. Inparticular embodiments, the candidate compound is identified as aninhibitor of IL-23R if the determined amount of binding to the humanIL-23R polypeptide or the rat IL-23R polypeptide is at least 1.5-fold,at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, atleast 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, atleast 50-fold, at least 100-fold, at least 200-fold, at least 500-fold,or at least 100-fold the determined amount of binding to the mouseIL-23R polypeptide. In particular embodiments, the candidate compound isa peptide. In particular embodiments, the peptide is a peptide of one ofthe formulas described herein. In particular embodiments, the humanIL-23 polypeptide or rat IL-23R polypeptide comprises or consists of thefull length human IL-23R or rat IL-23R protein, respectively. In otherembodiments, the human IL-23R polypeptide is a fragment of the fulllength human IL-23R protein, comprising 8 or more amino acid residueswithin the region of human IL-23R from about amino acid residue 230 toabout amino acid residue 370. In other embodiments, the rat IL-23Rpolypeptide is a fragment of the full length rat IL-23R protein,comprising 8 or more amino acid residues within the region of rat IL-23Rfrom about amino acid residue 245 to about amino acid residue 385.

In another embodiment, the present invention provides a new method toidentify an inhibitor (e.g., a peptide inhibitor) of IL-23R, based onidentifying an agent that binds to a region of human IL-23R or rat IL-23that is disrupted in mouse IL-23R by the presence of additional aminoacids from about amino acid residues 315 to about amino acid residue 340of the mouse IL23R protein, e.g., amino acid region NWQPWSSPFVHQTSQETGKR(see, e.g., FIG. 4). In certain embodiments, the method comprises: (a)determining an amount of binding of a candidate agent to a fragment ofhuman IL-23R polypeptide that falls within about amino acid residue 230to about amino acid residue 370, or to a fragment of rat IL-23Rpolypeptide that falls within about amino acid residue 245 to aboutamino acid residue 385; (b) determining an amount of binding of thecandidate agent to a negative control (e.g., a negative control peptideunrelated to human IL-23R or rat-IL-23R); and (c) comparing thedetermined amount of binding to the fragment of human IL-23R polypeptideor the fragment of rat IL-23R polypeptide to the determined amount ofbinding to the negative control, wherein if the determined amount ofbinding to the human IL-23R polypeptide fragment or the rat IL-23Rpolypeptide fragment is greater than the amount of binding to thenegative control, the candidate compound is an inhibitor of IL-23R. Inparticular embodiments, the candidate compound is identified as aninhibitor of IL-23R if the determined amount of binding to the humanIL-23R polypeptide fragment or the rat IL-23R polypeptide fragment is atleast 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, atleast 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, atleast 40-fold, at least 50-fold, at least 100-fold, at least 200-fold,at least 500-fold, or at least 100-fold the determined amount of bindingto the negative control. In particular embodiments, the candidatecompound is a peptide. In particular embodiments, the peptide is apeptide of one of the formulas described herein. In particularembodiments, the fragment of human IL-23R includes at least 8, at least12, at least 20, at least 50, or at least 100, or all amino acidresidues within the region of human IL-23R from about amino acid residue230 to about amino acid residue 370. In other embodiments, the fragmentof rat IL-23R polypeptide includes at least 8, at least 12, at least 20,at least 50, or at least 100, or all amino acid residues within theregion of rat IL-23R from about amino acid residue 245 to about aminoacid residue 385.

Methods of determining binding of a candidate compound to an IL-23polypeptide are known in the art and include but are not limited to invitro and cell-based binding assays, including those described herein.For example, a labeled candidate compound may be incubated with arecombinantly produced IL-23R polypeptide or negative control bound to asolid support under conditions and for a time sufficient to allowbinding, and then binding determined by measuring the amount of labelassociated with the bound IL-23R polypeptide.

Non-Invasive Detection of Intestinal Inflammation

The peptide inhibitors of the invention may be used for detection,assessment and diagnosis of intestinal inflammation by microPET imaging,wherein the peptide inhibitor is labeled with a chelating group or adetectable label, as part of a a non-invasive diagnostic procedure. Inone embodiment, a peptide inhibitor is conjugated with a bifunctionalchelator. In another embodiment, a peptide inhibitor is radiolabeled.The labeled peptide inhibitor is then administered to a subject orallyor rectally. In one embodiment, the labeled peptide inhibitor isincluded in drinking water. Following uptake of the peptide inhibitor,microPET imaging may be used to visualize inflammation throughout thesubject's bowels and digestive track.

Animal Models of IBD

The present invention includes models of animal disease, includinginflammatory diseases and disorders, such as inflammatory boweldiseases, e.g., Crohn's disease and colitis. As described in theaccompanying Examples, several animal models of inflammatory diseasesand disorders were developed.

In one embodiment, the present invention includes a method of assessingthe ability of a candidate compound to inhibit or reduce an inflammatorydisease disorder, comprising:

(a) providing to a rat an amount of dextran sulfate sodium (DSS)sufficient to induce IBD;

(b) providing to the rat an amount of a candidate compound; and

(c) measuring an amount of IBD symptoms present in the rat after beingprovided with the DSS and the candidate compound;

wherein if the amount of IBD symptoms measured in (c) are significantlylower than the amount measured in a control rat provided with the amountof DSS and either an amount of a control compound or no peptide (e.g.,vehicle control), the candidate compound inhibits or reduces theinflammatory disease or disorder.

In certain embodiments, the rat is provided with DSS for about 5 to 12days, e.g., about 9 days. In particular embodiments, the rat is providedwith DSS by providing to the rat ad lib exposure to drinking watercontaining DSS, e.g., about 1% to about 10% DSS, about 2% to about 5%DSS, or about 3% DSS. In particular embodiments, the rat is providedwith the test compound at about 5 mg/kg to about 100 mg/kg, or about 10mg/kg to about 50 mg/kg, or about 20 mg/kg or about 30 mg/kg. Inparticular embodiments, the rat is provided with test compound orally,e.g., in drinking water. In certain embodiments, the DSS assay isperformed as described in the accompanying Examples.

In another embodiment, the present invention includes a method ofassessing the ability of a candidate compound to inhibit or reduce aninflammatory disease disorder, comprising:

(a) providing to a rat an amount of 2,4,6-Trinitrobenzenesulfonic acid(TNBS) sufficient to induce IBD;

(b) providing to the rat an amount of a candidate compound; and

(c) measuring an amount of IBD symptoms present in the rat after beingprovided with the TNBS and the candidate compound;

wherein if the amount of IBD symptoms measured in (c) are significantlylower than the amount measured in a control rat provided with the amountof TNBS and either an amount of a control compound or no peptide (e.g.,vehicle control), the candidate compound inhibits or reduces theinflammatory disease or disorder.

In certain embodiments, the animals are provided with about 10 mg/kg toabout 200 mg/kg TNBS, e.g., about 10 mg/kg, about 20 mg/kg, about 30mg/kg, about 40 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg,about 80 mg/kg, about 90 mg/kg, about 100 mg/kg, about 120 mg/kg, about150 mg/kg or about 200 mg/kg of TNBS. In certain embodiments, the TNBSis in alcohol, e.g., in 45%-50% ethanol. In particular embodiments, theTNBS is administered intrarectally. In particular embodiments, the ratis provided with the test compound at about 5 mg/kg to about 100 mg/kg,or about 10 mg/kg to about 50 mg/kg, or about 20 mg/kg or about 30mg/kg. In particular embodiments, the rat is provided with the testcompound orally, e.g., in drinking water. In certain embodiments, theTNBS assay is performed as described in the accompanying Examples.

In particular embodiments IBD symptoms are measured immediatelyfollowing provision of the DSS or TNBS and candidate compound (or testcompound or no compound), or later, e.g., at about 3 days, 5 days, or 9days following initial provision of DSS or TNBS and candidate compound(or test compound or no compound). In particular embodiments, the IBDsymptoms measured include one or more of percent body weight loss, stoolconsistency, a quantitative hemoccult score, and ratio of colonweight:colon length. In certain embodiments, the IBD symptoms aremeasured using a disease activity index (DAI) score and/or ratio ofcolon weight:colon length, wherein the DAI score consists of ratingsfrom three parameters, including percent body weight loss, stoolconsistency, and a quantitative hemoccult score, and can achieve amaximum of three units.

In certain embodiments, a neutralizing anti-IL-23p19 antibody is used asa comparator or positive control.

In certain embodiments, to assess the extent of the inflammatoryresponse, animals are observed, e.g., daily, for clinical signs whichincluded percent body weight loss and signs of loose stools or diarrhea.Following a time period after inoculation of with DSS or TNBS (e.g., 5days, 6, days, or seven days), rats are sacrificed and their entirecolon length and colon weight from cecum to rectum recorded. Theseverity of colitis may be evaluated by a pathologist blinded to theidentity of treatments. In addition to the colon wall thickness, thegross colon damage may be assessed based on a 0-4 scale according toTable 19 below, and histopathological scores were determined based onbelow parameters (Tables 20 and 21).

In certain embodiments, IBD symptoms are measured in three groups ofrats, each with at least 3 animals, e.g., six animals each, wherein thethree groups include: vehicle, DSS or TNBS, and DSS or TNBS with apositive control (e.g., sulfasalazine administered at 100 mg/kg PO, QD).

EXAMPLES Example 1 Synthesis of Peptide Monomers

Peptide monomers of the present invention were synthesized using theMerrifield solid phase synthesis techniques on Protein Technology'sSymphony multiple channel synthesizer. The peptides were assembled usingHBTU(O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate),Diisopropylethylamine(DIEA) coupling conditions. For some amino acidcouplings PyAOP(7-Azabenzotriazol-1-yloxy)tripyrrolidinophosponiumhexafluorophosphate) and DIEA conditions were used. Rink Amide MBHAresin (100-200 mesh, 0.57 mmol/g) was used for peptide with C-terminalamides and pre-loaded Wang Resin with N-α-Fmoc protected amino acid wasused for peptide with C-terminal acids. The coupling reagents (HBTU andDIEA premixed) were prepared at 100 mmol concentration. Similarly aminoacids solutions were prepared at 100 mmol concentration. Peptideinhibitors of the present invention were identified based on medicalchemistry optimization and/or phage display and screened to identifythose having superior binding and/or inhibitory properties.

Assembly

The peptides were assembled using standard Symphony protocols. Thepeptide sequences were assembled as follows: Resin (250 mg, 0.14 mmol)in each reaction vial was washed twice with 4 ml of DMF followed bytreatment with 2.5 ml of 20% 4-methyl piperidine (Fmoc deprotection) for10 min. The resin was then filtered and washed two times with DMF (4 ml)and re-treated with N-methyl piperifine for additional 30 minute. Theresin was again washed three times with DMF (4 ml) followed by addition2.5 ml of amino acid and 2.5 ml of HBTU-DIEA mixture. After 45 min offrequent agitations, the resin was filtered and washed three timed withDMF (4 ml each). For a typical peptide of the present invention, doublecouplings were performed. After completing the coupling reaction, theresin was washed three times with DMF (4 ml each) before proceeding tothe next amino acid coupling.

Ring Closing Metathesis to Form Olefins

The resin (100 μmol) was washed with 2 ml of DCM (3×1 min) and then with2 ml of DCE (3×1 min) before being treated with a solution of 2 ml of a6 mM solution of Grubbs' first-generation catalyst in DCE (4.94 mg ml-1;20 mol % with regard to the resin substitution). The solution wasrefluxed overnight (12 h) under nitrogen before being drained. The resinwas washed three times with DMF (4 ml each); DCM (4 ml) before beingdried and cleavaed.

Cleavage

Following completion of the peptide assembly, the peptide was cleavedfrom the resin by treatment with cleavage reagent, such as reagent K(82.5% trigluoroacetic acid, 5% water, 5% thioanisole, 5% phenol, 2.5%1,2-ethanedithiol). The cleavage reagent was able to successfully cleavethe peptide from the resin, as well as all remaining side chainprotecting groups.

The cleaved peptides were precipitated in cold diethyl ether followed bytwo washings with ethyl ether. The filtrate was poured off and a secondaliquot of cold ether was added, and the procedure repeated. The crudepeptide was dissolved in a solution of acetonitrile:water (7:3 with 1%TFA) and filtered. The quality of linear peptide was then verified usingelectrospray ionization mass spectrometry (ESI-MS) (Micromass/Waters ZQ)before being purified.

Disulfide Bond Formation Via Oxidation

The peptide containing the free thiol (for example diPen) was assembledon a Rink Amide-MBHA resin following general Fmoc-SPPS procedure. Thepeptide was cleaved from the resin by treatment with cleavage reagent90% trifluoroacetic acid, 5% water, 2.5% 1,2-ethanedithiol, 2.5%tri-isopropylsilane). The cleaved peptides were precipitated in colddiethyl ether followed by two washings with ethyl ether. The filtratewas poured off and a second aliquot of cold ether was added, and theprocedure repeated. The crude peptide was dissolved in a solution ofacetonitrile:water (7:3 with 1% TFA) and filtered giving the wantedunoxidized peptide crude peptide

The crude, cleaved peptide with X4 and X9 possessing either Cys, Pen,hCys, (D)Pen, (D)Cys or (D)hCys, was dissolved in 20 ml of water:acetonitrile. Saturated Iodine in acetic acid was then added drop wisewith stirring until yellow color persisted. The solution was stirred for15 minutes, and the reaction was monitored with analytic HPLC and LCMS.When the reaction was completed, solid ascorbic acid was added until thesolution became clear. The solvent mixture was then purified by firstbeing diluted with water and then loaded onto a reverse phase HPLCmachine (Luna C18 support, 10 u, 100 A, Mobile phase A: water containing0.1% TFA, mobile phase B: Acetonitrile (ACN) containing 0.1% TFA,gradient began with 5% B, and changed to 50% B over 60 minutes at a flowrate of 15 ml/min). Fractions containing pure product were thenfreeze-dried on a lyophilyzer.

Lactam Bond Formation

100 mg of crude, cleaved peptide (approx. 0.12 mmol) is dissolved in 100ml of anhydrous dichloromethane. HOBt (1-Hydroxybenzotriazole hydrate)(0.24 mmol, 2 equivalents) is added followed by DIEA(N,N-Diisopropylethylamine) (1.2 mmol, 10equivalents) and TBTU(0-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate)(0.24 mmol, 2 equivalents). The mixture is stirredovernight and followed the reaction by HPLC. When the reaction iscompleted, dichloromethane is evaporated and diluted with water andAcetonitrile and then loaded onto a reverse phase HPLC machine (Luna C18support, 10 u, 100 A, Mobile phase A: water containing 0.1% TFA, mobilephase B: Acetonitrile (ACN) containing 0.1% TFA, gradient begins with 5%B, and is changed to 50% B over 60 minutes at a flow rate of 15 ml/min).Fractions containing pure product are then freeze-dried on alyophilyzer.

Triazole Bond Formation

The purified peptide containing the relevant amino acids alkyne andazide was stirred at room temperature in a phosphate/MeOH (2:1) at pH7.4 (1 mg per 2 ml). CuSO4.5H₂O (10 equiv.), and sodium ascorbate (10equiv.) was added and the mixture was agitated in at room temperaturefor 36 h. MeOH was removed and the solution was acidified to pH 3 with1% TFA water mix. The solution was then filtered before being loadedonto HPLC for peptide purification.

Thioether Bond Formation

The peptide containing the free thiol (eg Cys) and hSer(OTBDMS) wasassembled on a Rink Amide-MBHA resin following general Fmoc-SPPSprocedure. Chlorination was carried out by treating the resin with PPh₃(10 equiv.) and C13CCN (10 equiv.) in DCM for 2 h. The peptide wascleaved from the resin by treatment with cleavage reagent 90%trifluoroacetic acid, 5% water, 2.5% 1,2-ethanedithiol, 2.5%tri-isopropylsilane). The cleaved peptides were precipitated in colddiethyl ether followed by two washings with ethyl ether. The filtratewas poured off and a second aliquot of cold ether was added, and theprocedure repeated. The crude peptide was dissolved in a solution ofacetonitrile:water (7:3 with 1% TFA) and filtered giving the wanteduncyclized crude peptide

The crude peptide possessing a free thiol (eg Cys, Pen, hCys, (D)Pen,(D)Cys or (D)hCys) and the alkyl halide (hSer(Cl)) at either the X4 andX9 position or X9 and X4 position was dissolved in 0.1 M TRIS buffer pH8.5. Cyclization was allowed to take place overnight at RT. The solventmixture was then purified by first being diluted two-fold with water andthen loaded onto a reverse phase HPLC machine (Luna C18 support, 10 u,100 A, Mobile phase A: water containing 0.1% TFA, mobile phase B:Acetonitrile (ACN) containing 0.1% TFA, gradient began with 5% B, andchanged to 50% B over 60 minutes at a flow rate of 15 ml/min). Fractionscontaining pure product were then freeze-dried on a lyophilyzer.

Selenoether Bond Formation

Crude peptide containing the thiol protected-Selenium amino acid and thealkyl halide at X4 and X9 was dissolved in 0.1 M sodium phosphate bufferpH 5.5 containing DTT (40 equ.). Cyclization was allowed to take placeover 24 h at RT. The solution was then diluted two-fold with water, andthe final cyclized peptide was purified using RP-HPLC, affording theselenoether.

Diselenide Bond Formation

Diselenide precursor was dissolved in a solution of 0.1 M phosphatebuffer pH 6.0 and isopropanolcontaining DTT (40 equiv), and the reactionmixture was incubated at 37° C. After 20 h, additional DTT (10 equiv)was added to the reaction. After a total of 32 h, the cyclizationreaction was then diluted with twofold water, and the final cyclizedpeptide was purified using RP-HPLC, affording the diselenide.

Purification

Analytical reverse-phase, high performance liquid chromatography (HPLC)was performed on a Gemini C18 column (4.6 mm×250 mm) (Phenomenex).Semi-Preparative reverse phase HPLC was performed on a Gemini 10 μm C18column (22 mm×250 mm) (Phenomenex) or Jupiter 10 300A^(∘)C18 column(21.2 mm×250 mm) (Phenomenex). Separations were achieved using lineargradients of buffer B in A (Mobile phase A: water containing 0.15% TFA,mobile phase B: Acetonitrile (ACN) containing 0.1% TFA), at a flow rateof 1 mL/min (analytical) and 15 mL/min (preparative). Separations wereachieved using linear gradients of buffer B in A (Mobile phase A: watercontaining 0.15% TFA, mobile phase B: Acetonitrile (ACN) containing 0.1%TFA), at a flow rate of 1 mL/min (analytical) and 15 mL/min(preparative).

Linker Activation and Dimerization

Peptide monomer subunits were linked to form peptide dimer inhibitors asdescribed below.

Small Scale DIG Linker Activation Procedure:

5 mL of NMP was added to a glass vial containing IDA diacid (304.2 mg, 1mmol), N-hydroxysuccinimide (NHS, 253.2 mg, 2.2 eq. 2.2 mmol) and astirring bar. The mixture was stirred at room temperature to completelydissolve the solid starting materials. N, N′-Dicyclohexylcarbodiimide(DCC, 453.9 mg, 2.2 eq., 2.2 mmol) was then added to the mixture.Precipitation appeared within 10 min and the reaction mixture wasfurther stirred at room temperature overnight. The reaction mixture wasthen filtered to remove the precipitated dicyclohexylurea (DCU). Theactivated linker was kept in a closed vial prior to use fordimerization. The nominal concentration of the activated linker wasapproximately 0.20 M.

For dimerization using PEG linkers, there is no pre-activation stepinvolved. Commercially available pre-activated bi-functional PEG linkerswere used.

Dimerization Procedure:

2 mL of anhydrous DMF was added to a vial containing peptide monomer(0.1 mmol). The pH of the peptide was the adjusted to 8-9 with DIEA.Activated linker (IDA or PEG13, PEG 25) (0.48 eq relative to monomer,0.048 mmol) was then added to the monomer solution. The reaction mixturewas stirred at room temperature for one hour. Completion of thedimerization reaction was monitored using analytical HPLC. The time forcompletion of dimerization reaction varied depending upon the linker.After completion of reaction, the peptide was precipitated in cold etherand centrifuged. The supernatant ether layer was discarded. Theprecipitation step was repeated twice. The crude dimer was then purifiedusing reverse phase HPLC (Luna C18 support, 10 u, 100 A, Mobile phase A:water containing 0.1% TFA, mobile phase B: Acetonitrile (ACN) containing0.1% TFA, gradient of 15% B and change to 45% B over 60 min, flow rate15 ml/min). Fractions containing pure product were then freeze-dried ona lyophilyzer.

Example 2 Characterization of Peptide Inhibition of Binding ofInterleukin-23 to the Interleukin-23 Receptor

Peptide optimization was performed to identify peptide inhibitors ofIL-23 signalling that were active at low concentrations (e.g., IC50<10nM) while exhibiting gastrointestinal (GI) stability. Certain peptideswere tested to identify peptides that inhibit the binding of IL-23 tohuman IL-23R and inhibit IL-23/IL-23R functional activity, as describedbelow. Peptides tested included peptides containing a variety ofdifferent cyclization chemistries, including, e.g., cyclic amides (sidechain cyclizations), peptides containing a disulfide linkage, e.g.,between two Pen residues, and peptides containing a thioether linkage.Peptide inhibitors of the present invention include but are not limitedto peptides having any of the structures depicted herein. In addition,peptide inhibitors of the present invention include those having thesame amino acid sequence of the peptides or structures described herein,without being required to have the same or any N- or C-terminal“capping” groups, such as, e.g., Ac or NH₂.

Assays performed to determine peptide activity are described below, andthe results of these assays is provided in Tables 3A-3H, 4A and 4B,5A-5C, 6, 7, and 8. Human ELISA indicates the IL23-IL23R competitivebinding assay described below, Rat ELISA indicates the rat IL-23Rcompetitive binding ELISA assay described below, and pStat3HTRFindicates the DB cells IL-23R pSTAT3 cell assay described below. Thepeptides depicted in Tables 3B-3E are cyclized via a disulfide bridgeformed between two cysteine residues in these peptides. The peptidesdepicted in Table 3F are dimerized via a linker moiety or throughinternal cysteine moieties, as indicated. The peptides depicted inTables 4A and 4B are cyclized via the two Pen residues present in eachof these peptides. The peptides depicted in Table 5A are cyclized via athioether bond between the indicated amino acid residues. Table 5Bprovides an illustrative structure depicting thioether cyclization,which is indicated in the table by the term “Cyclo,” with the cyclicregion bracketed immediately following. The monomer subunits of thepeptide dimers shown in Table 5C are cyclized as indicated by the term“Cyclo” and linked to each other via the indicated linker. The peptidesshown in Table bare cyclized via ring closing metathesis of theindicated residues. Table 7 provides two illustrative structuresdepicting side chain cyclizations via cyclic amides, and the peptides inthis table are cyclized as indicated following the term “Cyclo.” Table 8depicts peptides cyclized via a cysteine residue and a Pen residue.

Peptide inhibitors of the present invention include both the cyclizedform of the peptides shown herein, as well as the non-cyclized forms.For certain peptides, the residue Abu is present where indicated,whereas in other embodiments related to the non-cyclized form, the Abumay be referred to as a hSer(C1) or homoSer residue.

IL23-IL23R Competitive Binding ELISA

An Immulon® 4HBX plate was coated with 50 ng/well of IL23R_huFC andincubated overnight at 4° C. The wells were washed four times with PBST,blocked with PBS containing 3% Skim Milk for 1 hour at room temperature,and washed again four times with PBST. Serial dilutions of test peptidesand IL-23 at a final concentration of 2 nM diluted in Assay Buffer (PBScontaining 1% Skim Milk) were added to each well, and incubated for 2hours at room temperature. After the wells were washed, bound IL-23 wasdetected by incubation with 50 ng/well of goat anti-p40 polyclonalantibodies (R&D Systems #AF309) diluted in Assay Buffer for 1 hour atroom temperature. The wells were again washed four times with PB ST. Thesecondary antibodies, HRP conjugated donkey anti-goat IgG (JacksonImmunoResearch Laboratories #705-035-147) diluted 1:5000 in Assay Bufferwas then added, and incubated for 30 minutes at room temperature. Theplate was finally washed as above. Signals were visualized with TMB OneComponent HRP Membrane Substrate, quenched with 2 M sulfuric acid andread spectrophotometrically at 450 nm. IC50 values for various testpeptides determined from these data are shown in Tables 3A-3H, 4A and4B, 5A-5C, 6, 7, and 8.

Rat IL-23R Competitive Binding ELISA

An assay plate was coated with 300 ng/well of Rat IL-23R_huFC andincubated overnight at 4° C. The wells were washed, blocked, and washedagain. Serial dilutions of test peptides and IL-23 at a finalconcentration of 7 nM were added to each well, and incubated for 2 hoursat room temperature. After the wells were washed, bound IL-23 wasdetected with goat anti-p40 polyclonal antibodies, followed by an HRPconjugated donkey anti-goat IgG. Signals were visualized with TMB OneComponent HRP Membrane Substrate and quenched with 2 M sulfuric acid.IC50 values for various test peptides determined from these data areshown in Tables 3G, 3H, 4A, 4B, 5B, 5C and 8.

DB Cells IL23R pSTAT3 Cell Assay

IL-23 plays a central role in supporting and maintaining Th17differentiation in vivo. This process is thought to mediated primarilythrough the Signal Transducer and Activator of Transcription 3 (STAT3),with phosphorylation of STAT3 (to yield pSTAT3) leading to upregulationof RORC and pro-inflammatory IL-17. This cell assay examines the levelsof pSTAT3 in IL-23R-expressing DB cells when stimulated with IL-23 inthe presence of test compounds. DB cells (ATCC #CRL-2289), cultured inRPMI-1640 medium (ATCC #30-2001) supplemented with 10% FBS and 1%Glutamine, were seeded at 5×10E5 cells/well in a 96 well tissue cultureplate. Serial dilutions of test peptides and IL-23 at a finalconcentration of 0.5 nM were added to each well, and incubated for 30minutes at 37° C. in a 5% CO₂ humidified incubator. Changes inphospho-STAT3 levels in the cell lysates were detected using the CisbioHTRF pSTAT3 Cellular Assay Kit, according to manufacturer's Two PlateAssay protocol. IC50 values determined from these data are shown inTables 3E, 3G, 3H, 4A, 4B, 5B, 5C, and 8 as absolute values or withinranges. Where not shown, data was not determined.

TABLE 3A Illustrative Non-cyclic Peptides and Activities ELISA IL23R/IL23 in SEQ ID nMoles NO. Sequence (IC50) 1Ac-[Aib]-[Aib]-TWQDYWLY-[Aib]-R-NH₂ >100,000 2 Ac-CAMTWQDYWLYGRC-NH₂7200 3 Ac-[Aib]-[Aib]-TWQDYWLYGR-NH₂ >100,000 4 Ac-AMTWQDYWLYGRK-NH₂4100 5 Ac-CAMTWQDYWLYGRCK-NH₂ 8500 6 Ac-KAMTWQDYWLYGR-NH₂ 5600 7Ac-KCAMTWQDYWLYGRC-NH₂ 10600 8 Ac-AMTWAibDYWLYGR-NH₂ >37,500 9Ac-AMTWQDYWLYGR-NH₂ 6100 10 Cyclo-[AMTWQDYWLYGR] Not active 11Hy-AATWQDYWLYGR-OH 7785 12 Hy-AMAWQDYWLYGR-OH 24225 13Hy-AMTAQDYWLYGR-OH N/A 14 Hy-AMTWADYWLYGR-OH 6248 15 Hy-AMTWQAYWLYGR-OH9589

TABLE 3B Illustrative Peptides Containing the CXXXXC Motif with IC50 >1uM in IL23-IL23R Competitive Binding ELISA SEQ ID NO. Sequence 87Hy-CSDWECYWHIFG-NH₂ 88 Hy-CETWECYWHSFS-NH₂ 89 Hy-CQSWECYWHYYG-NH₂ 90Hy-CSDWRCYWHVFG-NH₂ 91 Hy-CHTWVCYWHEFS-NH₂ 92 Hy-CTDWVCYWHEYS-NH₂ 93Hy-CQTWVCYWHTYG-NH₂ 94 Hy-CGNWECYWHVYG-NH₂ 95 Hy-CKDWKCYWHIYG-NH₂ 96Hy-CRTWVCYWHVFG-NH₂ 97 Hy-CAD-[1-Nal]-VCYWHTFG-NH₂ 98Hy-CAD-[2-Nal]-VCYWHTFG-NH₂ 99 Hy-CAD-[1-BIP]-VCYWHTFG-NH₂ 100Hy-CAD-[Tic]-VCYWHTFG-NH₂ 101 Hy-CAD-[βhW]-VCYWHTFG-NH₂ 102Hy-CADWVCY-[1-BIP]-HTFG-NH₂ 103 Hy-CADWVCY-[Tic]-HTFG-NH₂ 104Hy-CADWVCY-[βhW]-HTFG-NH₂ 105 Hy-CADWVCYAHTFG-NH₂ 106Hy-ACDWVCYWHTFG-NH₂ 107 Hy-ACDWCCYWCTFG-NH₂ 108 Hy-AADWCAYWCTFG-NH₂ 109Hy-CADWCCYWCTFG-NH₂ 110 Hy-CADWCCYWCTFG-NH₂ 111 Hy-CADWCCYWCTFG-NH₂ 112Hy-CADWVCYWHTF-NH₂ 113 Hy-CADWVCYWHT-NH₂ 114 Hy-CADWVCYW-NH₂ 115Hy-[β-Ala]-SCADWVCYWHTFG-OH 116 Ac-[(D)Lys]-SCADWVCYWHTFG-OH 117Ac-[(D)Lys]-[β-Ala]-CADWVCYWHTFG-OH 118 Hy-[AEA]-CADWVCYWHTFG-OH 119Ac-[(D)Lys]-CADWVCYWHTFG-OH 120 Ac-CKDWVCYWHTFG-OH 121Ac-CADWKCYWHTFG-OH 122 Ac-CADWVCYWKTFG-OH 123 Ac-CADWVCYWHKFG-OH 124Ac-CADWVCYWHTKG-OH 125 Ac-CADWVCYWHTF-[(D)Lys]-OH 126Ac-CADWVCYWHTFG-NH₂ 127 Hy-CADWVCY-[1-Nal]-HTF-OH 128Hy-CADWVCY-[1-Nal]-HT-[N-Me-Phe]-NH₂ 129Hy-CADWVCY-[1-Nal]-H-[Sarc]-F-OH 130 Hy-CADWVCY-[1-Nal]-[N-Me-His]-TF-OH131 Hy-CADWVCYWHTFGK-OH 132 Hy-C-[Sarc]-DWVCY-[1-Nal]-HTF-OH 133Hy-CAD-[N-Me-Trp]-VCY-[1-Nal]-HTF-OH 134Hy-CADW-[Sarc]-CY-[1-Nal]-HTF-OH 135 Hy-CADWVCY-[1-Nal]-HT-[(D)Phe]-OH136 Hy-CADWVCY-[1-Nal]-HTF-[Sarc]-OH 137 Ac-CATWVCYWHTFG-NH₂ 138Ac-CADWECYWHTFG-NH₂ 139 Ac-CADWVCYWHRCGWWGC-NH₂ 140Ac-CADWVCY-[1-Nal]-H-[(D)Ala]-FG-NH₂ 141Ac-CADWVCY-[1-Nal]-H-[Aib]-FG-NH₂ 142Ac-CADWVCY-[1-Nal]-H-[b-Ala]-FG-NH₂ 143 Ac-CADWVCY-[1-Nal]-FTFG-NH₂ 144Ac-CADWVCY-[1-Nal]-[(D)Ala]-TFG-NH₂ 145Ac-CADWVCY-[1-Nal]-H-[Aib]-[(D)Phe]-G-NH₂ 146Ac-CADWVCY-[1-Nal]-HTF-[Aib]-NH₂ 147Ac-CADWVCY-[1-Nal]-[N-Me-His]-[(D)Ala]-F- [Aib]-NH₂ 148Ac-CADWVCY-[1-Nal]-H-[AEP]-G-NH₂ 149Ac-CADWVCYW-[N-MeHis]-TFG-[AEA]-[(D)Lys]- NH₂ 150Ac-CADWVCY-[Aic]-HTFG-[AEA]-[(D)Lys]-NH₂ 151Ac-CADWVCY-[Bip]-HTFG-[AEA]-[(D)Lys]-NH₂ 152Ac-CQTWQCYW-[N-MeArg]-ENG-[AEA]-[(D)-Lys]- NH₂ 153Ac-CQTWQCYWR-[N-MeArg]-NG-[AEA]-[(D)-Lys]- NH₂ 154Ac-CQTWQCYWR-[N-MeLys]-NG-[AEA]-[(D)-Lys]- NH₂ 155Ac-CQTWQCYWR-[Sarc]-NG-[AEA]-[(D)-Lys]-NH₂ 156Ac-CQTWQCYWR-[(D)Glu]-NG-[AEA]-[(D)-Lys]-NH₂ 157Ac-CQTWQCYW-[(D)Arg]-ENG-[AEA]-[(D)-Lys]-NH₂ 158Ac-CQTWQCYW-[(D)Arg]-[(D)Glu]-NG-[AEA]- [(D)Lys]-NH₂ 159Ac-CQTWQCYW-[N-MeGlu]-NG-[AEA]-[(D)-Lys] 160 Ac-CADWVC-NH₂ 161Ac-CRDWQCYW-[N-MeArg]-KFG-[AEP]-[(D)-Lys]- NH₂ 162Ac-CRDWQCYWR-[(D)Lys]-FG-[AEP]-[(D)-Lys]-NH₂ 163Ac-CRDWQCYW-[(D)Arg]-KFG-[AEP]-[(D)-Lys]-NH₂ 164Ac-CRDWQCYW-[(D)Arg]-[(D)Lys]-FG-[AEP]-[(D)- Lys]-NH₂ 165Ac-CQTWQCYW-[N-MeArg]-ENG-[AEA]-[(D)-Lys]- NH₂

TABLE 3C Illustrative Peptides Containing the CXXXXC Motif with IC50 of500 nM to 1000 nM in IL23-IL23R Competitive Binding ELISA SEQ ID NO.Sequence 166 Hy-CTDWKCYWHEFG-NH₂ 167 Hy-CRTWTCYWHVYG-NH₂ 168Hy-CPNWECYWHRFG-NH₂ 169 Hy-CADWVCYWHTFG-NH₂ 170 Hy-CADWMCYWHEYG-NH₂ 171Hy-CTTWKCYWHQYG-NH₂ 172 Hy-CSNWECYWHHYG-NH₂ 173 Hy-CSDWVCYWHVYG-NH₂ 174Hy-CDTWKCYWHRQS-NH₂ 175 Hy-CADWVCY-[1-Nal]-HTFG-NH₂ 176Hy-CADWVCY-[2-Nal]-HTFG-NH₂ 177 Hy-CADWVCYWHTFG-NH₂ 178Ac-CADWVCYWHTFG-[(D)Lys]-OH 179 Ac-CADWVCYWHTFGAP-[(D)Lys]-OH 180Ac-CTDWKCYWHTFG-NH₂ 181 Ac-CRDWVCYWHTFG-NH₂ 182 Ac-CADWVCYWHEFG-NH₂ 183Ac-CADWVCYWHFHQLRDA-NH₂ 184 Ac-CADWVCYWHEHSERVG-NH₂ 185Ac-CADWVCYWHNHSEGSG-NH₂ 186 Ac-CADWVCYWHRSTGGQH-NH₂ 187Ac-[(D)Lys]-CRDWQCY-[1-Nal]-HTH-[Sarc]- [AEP]-[(D)Arg]-NH₂ 188Ac-TQFDCRTWECYWHTFG-NH₂ 189 Ac-GGVECNDWQCYWHTFG-NH₂ 190Ac-REGTCSTWKCYWHTFG-NH₂ 191 Ac-DTPRCRTWECYWHTFG-NH₂ 192Ac-GGGECENWECYWHTFG-NH₂ 193 Ac-GDHKCSSWECYWHTFG-NH₂ 194Ac-GSVHCMTWECYWHTFG-NH₂ 195 Ac-CADWVCY-[1-Nal]-VTFG-NH₂ 196Ac-CADWVCYW-[(D)His]-TFG-[AEA]-[(D)Lys]-NH₂

TABLE 3D Illustrative Peptides Containing the CXXXXC Motif with IC50<500 nM in IL23-IL23R Competitive Binding ELISA SEQ ID NO. Sequence 197Hy-CRDWQCYWHKFG-NH₂ 198 Hy-CSNWVCYWHTYG-NH₂ 199Ac-CADWVCYWHTFG-[β-Ala]-[(D)Lys]-OH 200Ac-CADWVCYWHTFG-[AEA]-[(D)Lys]-OH 201 Ac-CADWVCYWHTFG-OH 202Ac-CADWVCYWHTFG-[AEP]-(D)Arg]-OH 203 Ac-CADWVCYWHTFG-[AEP]-K-OH 204Ac-CADWVCYWHTFG-[Gaba]-[(D)Lys]-OH 205Ac-CADWVCYWHTFG-[Hexanoic]-[(D)Lys]-OH 206Ac-CADWVCYWHTFG-[(PEG)2-[(D)-Lys]-OH 207 Ac-CADWVCYWHTFGP-[(D)Lys]-OH208 Ac-CADWVCYWHTFG-[Azt]-[(D)-Lys]-OH 209 Ac-CADWVCYWHTFGA-[(D)Lys]-OH210 Ac-CADWVCYWHTFGAP-[(D)Lys]-OH 211 Ac-CADWVCYWHTFGA[Azt]-[(D)Lys]-OH212 Ac-CADWVCYWHTFGAA[(D)Lys]-OH 213 Ac-CRDWQCYWHKFG-[AEP]-[(D)Lys]-OH214 Ac-CATWQCYWHEYG-NH₂ 215 Ac-CKTWTCYWHEFG-NH₂ 216 Ac-CTTWTCYWHQYG-NH₂217 Ac-CRTWECYWHEFG-NH₂ 218 Ac-CRTWQCYWHEYG-NH₂ 219 Ac-CQTWQCYWRENG-NH₂220 Ac-CRTWECYWHEYG-NH₂ 221 Ac-CTTWECYWHEYG-NH₂ 222 Ac-CRTWECYWHEQS-NH₂223 Ac-CTTWECYWHQFG-NH₂ 224 Ac-CTTWECYWHEFG-NH₂ 225 Ac-CQTWECYWHLYG-NH₂226 Ac-CEDWKCYWHKYG-NH₂ 227 Ac-CTDWVCYWHTFG-NH₂ 228 Ac-CADWVCYWHTYG-NH₂229 Ac-CADWVCYWHRHADRVK-NH₂ 230 Ac-CADWVCYWHTFGER-NH₂ 231Ac-CADWVCYWHTHGER-NH₂ 232 Ac-DTPRCRTWECYWHTFG-NH₂ 233Ac-CQTWVCYWRENG-[AEA]-[(D)-Lys]-NH₂ 234Ac-CQTWQCYWRENG-[AEA]-[(D)-Lys]-NH₂ 235Ac-CQTWQCYWRTNG-[AEA]-[(D)-Lys]-NH₂ 236Ac-CQTWQCYWRKNG-[AEA]-[(D)-Lys]-NH₂ 237Ac-CQTWQCYWRRNG-[AEA]-[(D)-Lys]-NH₂ 238Ac-CQTWQCYWR-[Dapa]-NG-[AEA]-[(D)-Lys]-NH₂ 239Ac-CQTWQCYWR-[Orn]-NG-[AEA]-[(D)-Lys]-NH₂ 240Ac-CRTWQCYWRKFG-[AEA]-[(D)-Lys]-NH₂ 241Ac-CQTWQCYWRENG-[AEA]-[(D)Arg]-NH₂ 242Ac-CQTWQCYWRENG-[AEA]-[(D)-Lys]-NH₂ 243Ac-CQDWQCYWRENG-[AEA]-[(D)-Lys]-NH₂ 244Ac-CQTWQCYWRENG-[AEA]-[(D)-Lys]-NH₂ 245Ac-CQTWQCYWRTNG-[AEA]-[(D)-Lys]-NH₂ 246Ac-CQTWVCYWRENG-[AEA]-[(D)-Lys]-NH₂ 247Ac-CQTWQCYWRKNG-[AEA]-[(D)-Lys]-NH₂ 248 Ac-CQTWQCYW-[Cav]-ENG-NH₂ 249Ac-CQTWQCYW-[Cpa]-ENG-NH₂ 250 Ac-CQTWQCYWLENG-NH₂ 251Ac-CQTWQCYW[-hLeu]-ENG-NH₂ 252 Ac-CQTWQCYWR-[K-Ac]-NG-NH₂ 253Hy-CRTWQCYWRKFG-NH₂

TABLE 3E IC50 of Illustrative Peptides Containing the CXXXXC Motif withActivities ELISA IL23R/ pStat3 SEQ IL23 HTRF ID in in NO. Sequence nMnMoles 169 Hy-CADWVCYWHTFG-NH₂ **** **** 178 Ac-CADWVCYWHTFG-[(D)Lys]-OH**** **** 210 Ac-CADWVCYWHTFGAP-[(D)Lys]-OH **** ND 211Ac-CADWVCYWHTFGA[Azt]-[(D)Lys]-OH **** ND 180 Ac-CTDWKCYWHTFG-NH₂ ******** 196 Ac-CADWVCYW-[(D)His]-TFG-[AEA]- **** **** [(D)Lys]-NH₂ 281 DIGdimererisation through ***** ***** N-termina Lysine (Ac-KMTWQDYWLYGR-NH₂)₂ 284 DIG dimererisation through ***** ***** C-terminal Lysine (Ac-AMTWQDYWLYGK-NH₂)₂ * = <10 nM; ** = 10-25 nM *** = 25-100 nM, ****= 100-1000 nM, ***** = 1000-10,000 nM.

TABLE 3F IC50 of Illustrative Peptide Dimers Human IL23R/IL23 SEQ IDELISA NO. Linker Moiety Sequence (nM) 277 oxidized dimer through(Hy-FPTWEWYWCNRD-NH₂)₂ ***** the cysteine 278 oxidized dimer through(Hy-ALTWEFYWLCRE-NH₂)₂ >10,000 the cysteine 291 DIG through Lysine(Hy-[βAla]SCADWVCYWHTFG-OH)₂DIG >10,000 292 DIG through Lysine(Ac-[(D)Lys]-SCADWVCYWHTFG-OH)₂ >10,000 DIG 293 DIG through Lysine(Ac-(D)Lys-[βAla]-CADWVCYWHTFG- >10,000 OH)₂DIG 294 DIG through Lysine(Hy-AEA-CADWVCYWHTFG-OH)₂DIG >10,000 295 DIG through Lysine(Ac-[(D)Lys]-CADWVCYWHTFG-OH)₂ >10,000 DIG 296 DIG through Lysine(Ac-CKDWVCYWHTFG-OH)₂DIG >10,000 297 DIG through Lysine(Ac-CADWKCYWHTFG-OH)₂DIG >10,000 298 DIG through Lysine(Ac-CADWVCYWKTFG-OH)₂DIG 299 DIG through Lysine(Ac-CADWVCYWHKFG-OH)₂DIG >10,000 300 DIG through Lysine(Ac-CADWVCYWHTKG-OH)₂DIG ***** 301 DIG through Lysine(Ac-CADWVCYWHTFDK-OH)₂DIG >10,000 302 DIG through Lysine(Ac-CADWVCYWHTFGDK)₂DIG ***** 303 DIG through Lysine(Ac-CADWVCYWHTFG-[β-Ala]-[(D)Lys]- *** OH)₂DIG 304 DIG through Lysine(Ac-CADWVCYWHTFG-[AEA]-[(D)Lys]- *** OH)₂DIG 305 DIG through C terminal(Hy-CADWVCYWHTFGK-OH)₂DIG ***** Lysine 306 PEG25 through Lysine(Hy-[βAla]-SCADWVCYWHTFG-OH)₂ PEG25 307 PEG25 through Lysine(Ac-[(D)Lys]-SCADWVCYWHTFG-OH)₂ 308 PEG25 through Lysine(Ac-(D)Lys)-[βAla]-CADWVCYWHTFG- OH)₂ 309 PEG25 through Lysine(Hy-[AEA]-CADWVCYWHTFG-OH)₂ 310 PEG25 through Lysine(Ac-[(D)Lys]-CADWVCYWHTFG-OH)₂ 311 PEG25 through Lysine(Ac-CKDWVCYWHTFG-OH)₂ 312 PEG25 through Lysine (Ac-CADWKCYWHTFG-OH)₂ 313PEG25 through Lysine (Ac-CADWVCYWKTFG-OH)₂ 314 PEG25 through Lysine(Ac-CADWVCYWHKFG-OH)₂ 315 PEG25 through Lysine (Ac-CADWVCYWHTKG-OH)₂ 316PEG25 through Lysine (Ac-CADWVCYWHTF-[(D)Lys]-OH)₂ 317 PEG25 throughLysine (Ac-CADWVCYWHTFG-[(D)Lys]-OH)₂ 318 PEG25 through Lysine(Ac-CADWVCYWHTFG-[bAla]-[(D)Lys]- OH)₂ 319 PEG25 through Lysine(Ac-CADWVCYWHTFG-[AEA]-[(D)Lys]- OH)₂ 320 PEG25 through C-(Hy-CADWVCYWHTFGK-OH)₂ terminal Lysine * = <10 nM; ** = 10-25 nM ***= 25-100 nM, **** = 100-1000 nM, ***** = 1000-10,000 nM.

TABLE 3G IC50 of Illustrative Peptides Containing theCXXWXCXXXXX-[(D)Lys] Motif Human Rat ELISA ELISA IL23/ IL23/ pStat3 SEQIL23R IL23R HTRF ID NO. Sequence (nM) (nM) (nM) 16Ac-CQDWQCYWR-[Cha]-FG-[AEA]-[(D)Lys]-NH₂ 113 17Ac-CQTWQCYWR-[Ogl]-FG-[AEA]-[(D)Lys]-NH₂ 206 18Ac-CQTWQCYWK-[Dap]-FG-[AEA]-[(D)Lys]-NH₂ 32 19Ac-CQTWQCYWH-[Dap]-FG-[AEA]-[(D)Lys]-NH₂ 49 59 20Ac-CQTWQCYWRLFG-[AEA]-[(D)Lys]-NH₂ 51 47 21Ac-CQTWQCYW-[hArg]-[Dap]-FG-[AEA]-[(D)Lys]-NH₂ 56 22Ac-CQTWQCYW-[Cit]-[Dap]-FG-[AEA]-[(D)Lys]-NH₂ 25 23Ac-CQTWQCYWRVFG-[AEA]-[(D)Lys]-NH₂ 39 62 14 24Ac-CQTWQCYWR-[Dap]-[Tic]-G-[AEA]-[(D)Lys]-NH₂ 892 65 12 25Ac-CQTWQCY-[Tic]-[Orn]-KFG-[AEA]-[(D)Lys]-NH₂ >30000 26Ac-CQTWQCYWR-[Dab]-FG-[AEA]-[(D)Lys]-NH₂ 37 27Ac-CQTWQCYW-[Orn]-[Dap]-FG-[AEA]-[(D)Lys]-NH₂ 79 276 37 28Ac-CQTWQCYWHENGA-[(D)Lys]-NH₂ 220 29 Ac-CRTWQCYWRENGA-[(D)Lys]-NH₂ 10286 17 30 Ac-CRTWQCYWREYGA-[(D)Lys]-NH₂ 78 80 8 31Ac-C-[N-MeAla]-DWVCYWHTFG-[AEA]-[(D)Lys]-NH₂ 183 32Ac-CADWVCYWRKFG-[βAla]-[(D)Lys]-NH₂ 57 33(1) 13 33Ac-CADWVCYW-[Cit]-KFG-[β-Ala]-[(D)Lys]-NH₂ 52 29 34Ac-CADWVCYW-[Cit]-[Tle]-FG-[β-Ala]-[(D)Lys]-NH₂ 518 35Ac-CADWVCYW-[Cit]-[Tba]-FG-[β-Ala]-[(D)Lys]-NH₂ 153 36Ac-CADWVCYW-[Cit]-[Cha]-FG-[β-Ala]-[(D)Lys]-NH₂ 223 37Ac-CADWVCY-[1-Nal]-[Cit]-VFG-[β-Ala]-[(D)Lys]-NH₂ 79 22 38Ac-CADWVCYW-[Cit]-VFG-[β-Ala]-[(D)Lys]-NH₂ 124 39Ac-CADWVCYW-[Cit]-[Chg]-FG-[β-Ala]-[(D)Lys]-NH₂ >30000 40Ac-CADWVCYW-[Cit]-[βAla]-FG-[β-Ala]-[(D)Lys]-NH₂ 2584 41Ac-CADWVCYW-[Tle]-[Tle]-FG-[β-Ala]-[(D)Lys]-NH₂ ~30000 42Ac-CADWVCYW-[Tle]-KFG-[β-Ala]-[(D)Lys]-NH₂ 199 43Ac-CQTWQCYW-[(D)Ala]-VFG-[AEA]-[(D)Lys]-NH₂ 232 44Ac-CQTWQCYW-[βAla]-VFG-[AEA]-[(D)Lys]-NH₂ 2207 45Ac-CQTWQCYW-[(D)Leu]-VFG-[AEA]-[(D)Lys]-NH₂ 188 46Ac-CQTWQCYW-[(D)Phe]-VFG-[AEA]-[(D)Lys]-NH₂ 848 47Ac-CQTWQCYW-[(D)Asn]-VFG-[AEA]-[(D)Lys]-NH₂ 61 48Ac-CQTWQCYW-[(D)Thr]-VFG-[AEA]-[(D)Lys]-NH₂ 3662 49Ac-CQTWQCYW-[(D)Asp]-VFG-[AEA]-[(D)Lys]-NH₂ 129 50Ac-CQTWQCYW-[Cit]-[(D)Leu]-FG-[AEA]-[(D)Lys]-NH₂ 709 51Ac-CQTWQCYW-[Cit]-[(D)Phe]-FG-[AEA]-[(D)Lys]-NH₂ 1304 52Ac-CQTWQCYW-[Cit]-[(D)Asn]-FG-[AEA]-[(D)Lys]-NH₂ 269 53Ac-CQTWQCYW-[Cit]-[(D)Thr]-FG-[AEA]-[(D)Lys]-NH₂ 1214 54Ac-CQTWQCYW-[Agp]-VNG-[AEA]-[(D)Lys]-NH₂ 241 55Ac-CQTWQCY-[α-MeTrp]-RVNG-[AEA]-[(D)Lys]-NH₂ ~6000 56Ac-CQTWQCY-[α-MeTrp]-[Cit]-[hLeu]-NG-[AEA]- ~6000 [(D)Lys]-NH₂ 57Ac-CQTWQCYW-[Cit]-VNG-[AEA]-[(D)Lys]-NH₂ 73 58Ac-CQTWQCYW-[Agp]-[Dap]-NG-[AEA]-[(D)Lys]-NH₂ 38 59Ac-CQTWQCYW-[Cit]-VF-[(D)Ala]-[AEA]-[(D)Lys]-NH₂ 397 60Ac-CQTWQCYW-[Cit]-VF-[(D)Leu]-[AEA]-[(D)Lys]-NH₂ 444 61Ac-CQTWQCYW-[Cit]-VF-[(D)Phe]-[AEA]-[(D)Lys]-NH₂ 784 62Ac-CQTWQCYW-[Cit]-VF-[(D)Asn]-[AEA]-[(D)Lys]-NH₂ 93 63Ac-CQTWQCYW-[Cit]-VF-[(D)Thr]-[AEA]-[(D)Lys]-NH₂ 518 64Ac-CQTWQCYW-[Cit]-VF-[(D)Asp]-[AEA]-[(D)Lys]-NH₂ 551 65Ac-C-[N-MeArg]-TWQCYWRVFG-[AEA]-[(D)Lys]-NH₂ 149 192 107 66Ac-C-[N-MeGln]-TWQCYWRVFG-[AEA]-[(D)Lys]-NH₂ 69 85 101 67Ac-C-[Cit]-TWQCYWRVFG-[AEA]-[(D)Lys]-NH₂ 50 76 107 68Ac-CADWVCYW-[Orn]-[Dap]-FG-[AEA]-[(D)Lys]-NH₂ 382 69Ac-CADWVCY-[1-Nal]-[Orn]-[Dap]-FG-[AEA]-[(D)Lys]- 302 NH₂ 70Ac-CADWVCY-[(D)Trp]-[Orn]-[Dap]-FG-[AEA]- >30000 [(D)Lys]-NH₂ 71Ac-CADWVCY-[hPhe]-[Orn]-[Dap]-FG-[AEA]-[(D)Lys]- ~30000 NH₂ 72Ac-CADWVCY-[Bip]-[Orn]-[Dap]-FG-[AEA]-[(D)Lys]- >30000 NH₂ 73Ac-CADWVCY-[Phe(3,5-F₂)]-[Orn]-[Dap]-FG-[AEA]- ~6000 [(D)Lys]-NH₂ 74Ac-CADWVCY-[Phe(CONH₂)]-[Orn]-[Dap]-FG-[AEA]- ~6000 [(D)Lys]-NH₂ 75Ac-CADWVCY-[Phe(4-CF₃)]-[Orn]-[Dap]-FG-[AEA]- >1000 [(D)Lys]-NH₂ 76Ac-CADWVCY-[Phe(2,4-Me₂)]-[Orn]-[Dap]-FG-[AEA]- 1525 [(D)Lys]-NH₂ 77Ac-CMTWQCYWLYGR-[AEA]-[(D)Lys]-NH₂ 398 77Hy-CMTWQCYWLYGR-[AEA]-[(D)Lys]-NH₂ >30000 78Ac-CADWVCY-[βhTrp]-[Orn]-[Dap]-FG-[AEA]-[(D)Lys]- ~6000 NH₂ 79Ac-CADWVCYW-[Orn]-[α-MeLeu]-FG-[AEA]-[(D)Lys]- ~6000 NH₂ 80Ac-CADWVCYW-[Orn]-[β-spiral-pip]-FG-[AEA]- 579 [(D)Lys]-NH₂ 81Ac-CADWVCY-[4-Phenylcyclohexylalanine]-[Orn]-[Dap]- >3000FG-[AEA]-[(D)Lys]-NH₂ 82 Ac-CADWVCYW-[Orn]-[Aib]-FG-[AEA]-[(D)Lys]-NH₂1085 83 Ac-CADWVCYW-[Orn]-[DiethylGly]-FG-[AEA]- ~6000 [(D)Lys]-NH₂ 84Ac-CADWVCY-[α-MePhe(4-F)]-[Orn]-[Dap]-FG-[AEA]- >30000 [(D)Lys]-NH₂ 85Ac-CQTWQCY-[βhPhe]-RVNG-[AEA]-[(D)Lys]-NH₂ >30000 86Ac-CQTWQCY-[β(1-Nal)]-RVNG-[AEA]-[(D)Lys]-NH2 >30000 321Ac-CQTWQCY-[βhTyr]-RVNG-[AEA]-[(D)Lys]-NH₂ >30000 322Ac-CQTWQCY-[βhPhe(4-F)]-RVNG-[AEA]-[(D)Lys]-NH₂ >30000 323Ac-CQTWQCY-[βNva(5-Phenyl)]-RVNG-[AEA]- >30000 [(D)Lys]-NH₂ 324Ac-CQTWQCY-[Phe(3,4-Cl₂)]-RVNG-[AEA]-[(D)Lys]- >30000 NH₂ 325Ac-CQTWQCY-[Tqa]-RVNG-[AEA]-[(D)Lys]-NH₂ >30000 326Ac-CQTWQCYWR-[βhLeu]-NG-[AEA]-[(D)Lys]-NH₂ 224 327Ac-CQTWQCYWR-[Aib]-NG-[AEA]-[(D)Lys]-NH₂ 1065 328Ac-CQTWQCYWR-[βhAla]-NG-[AEA]-[(D)Lys]-NH₂ 457 329Ac-CQTWQCYWR-[βhVal]-NG-[AEA]-[(D)Lys]-NH₂ 328 330Ac-CQTWQCYWR-[β-spiral-pip]-NG-[AEA]-[(D)Lys]- 405 NH₂ 331Ac-CQTWQCYWR-[βGlu]-NG-[AEA]-[(D)Lys]-NH₂ 250 332Ac-CQTWQCYW-[βhLeu]-VNG-[AEA]-[(D)Lys]-NH₂ 311 333Ac-CQTWQCYW-[βAib]-VNG-[AEA]-[(D)Lys]-NH₂ 2903 334Ac-CQTWQCYW-[βhAla]-VNG-[AEA]-[(D)Lys]-NH₂ 355 335Ac-CQTWQCYW-[βhVal]-VNG-[AEA]-[(D)Lys]-NH₂ 501 336Ac-CQTWQCYW-[β-spiral-pip]-VNG-[AEA]-[(D)Lys]- >6000 NH₂ 337Ac-CQTWQCYW-[βhArg]-VNG-[AEA]-[(D)Lys]-NH₂ 922 338Ac-MRTWQ-[MeCys]-YWRKFG-[AEA]-[(D)Lys]-NH₂ 4251 339Ac-ACDWVCYWRKFG-[AEA]-[(D)Lys]-NH₂ 630 340Ac-SRTWQSYWRKFG-[AEA]-[(D)Lys]-NH₂ 2816 341Ac-CDWVCYWRKFG-[AEA]-[(D)Lys]-NH₂ 664 342Ac-ARTWQ-[MeCys]-YWRKFG-[AEA]-[(D)Lys]-NH₂ 7571 343Ac-ARTWQAYWRKFG-[AEA]-[(D)Lys]-NH₂ 3194 344Ac-CQTWQCYW-[hLeu]-EN-[AEA]-[(D)Lys]-NH₂ 132 345Ac-CQTWQCYW-[hLeu]-ENG-[AEA]-[(D)Lys]-NH₂ 222 346Ac-CSTWECYWRVYG-[AEA]-[(D)Lys]-NH₂ 47 347Ac-C-[Orn]-TWQCYWRVFG-[AEA]-[(D)Lys]-NH₂ 22 69 95 348Ac-CQTWQCYW-[Orn]-[Dap]-FG-[AEA]-[(D)Lys]-NH₂ 96 349Ac-C-[N-MeAsn]-TWQCYWRVFG-[AEA]-[(D)Lys]-NH₂ 148 350Ac-C-[N-MeLys]-TWQCYWRVFG-[AEA]-[(D)Lys]-NH₂ 80 351Ac-C-[Dab]-TWQCYWRVFG-[AEA]-[(D)Lys]-NH₂ 23 51 99 352Ac-CQTWQCYY-[Orn]-[Dap]-FG-[AEA]-[(D)Lys]-NH₂ 710 353Ac-CSTWQCYW-[Orn]-[Dap]-YG-[AEA]-[(D)Lys]-NH₂ 371 354Ac-CSTWECYW-[Cit]-[Dap]-YG-[AEA]-[(D)Lys]-NH₂ 74 355Ac-CQTWQCFF-[Orn]-[Dap]-FG-[AEA]-[(D)Lys]-NH₂ 4274 356Ac-CPTWQCYWRVFG-[AEA]-[(D)Lys]-NH₂ 422 357Ac-CSTWECYW-[Orn]-[Dab]-YG-[AEA]-[(D)Lys]-NH₂ 338 358Ac-CSTWECYWRVFG-[AEA]-[(D)Lys]-NH₂ 48 359Ac-CLTWQCYWRVFG-[AEA]-[(D)Lys]-NH₂ 134 360Ac-CQTWQCYF-[Orn]-[Dap]-FG-[AEA]-[(D)Lys]-NH₂ 1885 361Ac-CNTWQCYWRVFG-[AEA]-[(D)Lys]-NH₂ 21 79 96 362Ac-C-[Dap]-TWQCYWRVFG-[AEA]-[(D)Lys]-NH₂ 31 100 363Ac-C-[N-Me-Ala]-TWQCYWRVFG-[AEA]-[(D)Lys]-NH₂ 139 364Ac-CKTWQCYWRVFG-[AEA]-[(D)Lys]-NH₂ 40 365Ac-CQDWQCYWR-[Cha]-FG-[AEA]-[(D)Lys]-NH₂ 113 366Ac-CQTWQCYWR-[Ogl]-FG-[AEA]-[(D)Lys]-NH₂ 206 367Ac-CQTWQCYWK-[Dap]-FG-[AEA]-[(D)Lys]-NH₂ 32 368Ac-CQTWQCYWH-[Dap]-FG-[AEA]-[(D)Lys]-NH₂ 49 59 369Ac-CQTWQCYWRLFG-[AEA]-[(D)Lys]-NH₂ 51 47 370Ac-CQTWQCYW-[hArg]-[Dap]-FG-[AEA]-[(D)Lys]-NH₂ 56

TABLE 3H IC50 of Illustrative Peptides Containing the CXXWXCXXXX MotifHuman Rat IL23/ IL23/ IL23R IL23R pStat3 SEQ ID ELISA ELISA HTRF NO.Sequence (nM) (nM) (nM) 371 Ac-CSTWECYWRTFG-NH₂ 252 372Ac-CDSWECYWRTYG-NH₂ 366 373 Ac-CSTWECYWHTYG-NH₂ 181 286 97 374Ac-CKTWTCYWHTYG-NH₂ 381 375 Ac-CRTWECYWHEYS-NH₂ 416 376Ac-CRTWTCYWHEYG-NH₂ 434 377 Ac-CFTWQCYWHEYS-NH₂ 515 378Ac-CQTWQCYW-[3-Pal]-ENG-NH₂ 56 20 101 379 Ac-CQTWQC-NH₂ >30000 380Ac-CRTWQC-NH₂ >30000 381 Ac-CADWVCY-NH₂ >30000 382Ac-CADWVCYW-NH₂ >30000 383 Ac-CADWVCYWH-NH₂ ~30000 384 Ac-CADWVCYWHT-NH₂4795 385 Ac-CADWVCYWHTF-NH₂ 3277 386 Ac-CMTWQCYWLYGR-NH₂ 613 387Ac-CRTWQCYWHEFG-NH₂ 388 Ac-CRTWECYWHTFG-NH₂ 389 Ac-CQTWQCYWHEFG-NH₂ 390Ac-CRTWQCYWQQFGGE-NH₂ 81 391 Ac-CRSWQCYWLNFGPD-NH₂ 101 392Ac-CRTWQCYWLKMGDS-NH₂ 39 393 Ac-CQTWQCYWIKRDQG-NH₂ 67 394Ac-CSTWQCYWLKHGGE-NH₂ 19 24 2 395 Ac-CSTWECYWSQRADQ-NH₂ 240 396Ac-CQTWECYWRTFGPS-NH₂ 58 397 Ac-CRTWQCYWQEKGTD-NH₂ 118 398Ac-CQTWQCYWLDSLGD-NH₂ 93 399 Ac-CRTWQCYWTKFGSEP-NH₂ 87 57 1051Ac-CRSWQCYWNKFGADD-NH₂ 142 1052 Ac-CHTWQCYWLNFGDEE-NH₂ 323 1053Ac-CRTWQCYWLNFGNEQ-NH₂ 127 1054 Ac-CRTWQCYWSEFGTGE-NH₂ 180 778 103 1055Ac-CRTWQCYWLRLGDEG-NH₂ 352 483 181 1056 Ac-CHTWQCYWSTLGPEA-NH₂ 222 1057Ac-CSTWQCYWSKQSGGS-NH₂ 133 204 89 1058 Ac-CHTWQCYWLNNGTSQ-NH₂ 113 1059Ac-CHTWQCYWRANDGRD-NH₂ 210 1060 Ac-SGCRTWQCYWHEFG-NH₂ 390 1061Ac-NKCRTWQCYWHEYG-NH₂ 112 1062 Ac-SGCRTWECYWHEYG-NH₂ 257 1063Ac-DACRTWECYWHKFG-NH₂ 165 1064 Ac-PECRTWECYWHKFG-NH₂ 197 1065Ac-QVCQTWECYWREFG-NH₂ 145 1066 Ac-DRCVTWECYWREFG-NH₂ 217 1067Ac-ADQCRTWQCYWHEFG-NH₂ 228 1068 Ac-KENCRTWECYWREFG-NH₂ 148 1069Ac-VQECSTWQCYWRTFG-NH₂ 138 1070 Ac-GEECSTWQCYWRKFG-NH₂ 53 24 1071Ac-DGSCRTWQCYWHQFG-NH₂ 240 1072 Ac-NADCHSWECYWREFG-NH₂ 872 1073Ac-ERNCSTWECYWRAFG-NH₂ 855 1074 Ac-RVGCSTWECYWREFG-NH₂ 417 1075Ac-KANCRTWQCYWRKFE-NH₂ 412 1076 Ac-YEDCRTWQCYWENFG-NH₂ 280 1077Ac-CQTWQCYWRNFGDS-NH₂ 1078 Ac-CQTWQCYWRNFESG-NH₂ 1079Ac-CQDWQCYWREFGPG-NH₂ 1080 Ac-CQDWQCYWRSFGPQ-NH₂ 1081Ac-CQTWQCYWRTLGPS-NH₂ 1082 Ac-CRTWQCYWQNFG-NH₂ 235 1083Ac-CGTWQCYWRTFGPS-NH₂ 76 1084 Ac-CSTWQCYWHKFGNE-NH₂ 182 1085Ac-CRTWECYWRTYGPS-NH₂ 116 1086 Ac-CRTWQCYWWENSQM-NH₂ 99 1087Ac-CQTWQCYWREFGGG-NH₂ 165 1088 Ac-CQTWQCYWRTHGDR-NH₂ 83 1089Ac-CRDWQCYWLSRP-NH₂ 330 1090 Ac-CQTWQCYW-[K(Palm)]-ENG-NH₂ 4880 1091Ac-CQTWQCYW-[K(PEG8)]-ENG-NH₂ 153 1092 Ac-CQTWQCYW-[hLeu]-EQG-NH₂ 1281093 Ac-CQTWQC-[(D)Tyr]-W-[hLeu]-ENG-NH₂ >30000 1094Ac-CQTWQC-[(N-MeTyr]-W-[hLeu]-ENG-NH₂ >30000 1095Ac-CQTWQC-[Tic-OH]-W-[hLeu]-ENG-NH₂ >30000 1096Ac-CQTWQCEW-[hLeu]-ENG-NH₂ >30000 1097 Ac-CQTWQCTW-[hLeu]-ENG-NH₂ >300001098 Ac-CQTWQC-[Cha]-W-[hLeu]-ENG-NH₂ ~6000 1099Ac-CQTWQCYW-[α-MeLeu]-ENG-NH₂ 22 27 5 1100 Ac-CQTWQCYW-[(D)Leu]-ENG-NH₂319 1101 Ac-CQTWQCYW-[hLeu]-ENG-[(D)Lys]-NH₂ 121 1102Ac-CQTWQCYW-[hLeu]-ENG-OH 317 1103 Ac-CQTWQCYW-[hLeu]-ENE-NH₂ 222 1002310 1104 Ac-CQTWQCYW-[hLeu]-ENR-NH₂ 93 1105 Ac-CQTWQCYW-[hLeu]-ENF-NH₂82 182 69 1106 Ac-CQTWQCYW-[hLeu]-ENP-NH₂ 253 114 31 1107Ac-CQTWQCYW-[hLeu]-ENQ-NH₂ 347 1108 Ac-CQTWQCYW-[hLeu]-ENL-NH₂ 45 1109Ac-CQTWQCYW-[hLeu]-EEG-NH₂ 135 53 16 1110 Ac-CQTWQCYW-[hLeu]-ERG-NH₂ 647400 Ac-CQTWQCYW-[hLeu]-EPG-NH₂ 108 140 27 401 Ac-CQTWQCYW-[hLeu]-ELG-NH₂158 402 Ac-CQTWQCYW-[hLeu]-ETG-NH₂ 818 403 Ac-CQTWQCYW-[hLeu]-FNG-NH₂395 404 Ac-CQTWQCYW-[hLeu]-PNG-NH₂ 4828 405 Ac-CQTWQCYW-[hLeu]-NNG-NH₂89 26 406 Ac-CQTWQCYW-[hLeu]-LNG-NH₂ 78 407 Ac-CQTWQCYW-[hLeu]-TNG-NH₂109 408 Ac-CQTWQCYWFENG-NH₂ 185 409 Ac-CQTWQCYWPENG-NH₂ >30000 410Ac-CQTWQCYWQENG-NH₂ 173 411 Ac-CQTWQCYWTENG-NH₂ 114 412Ac-CQTWQCYWEENG-NH₂ 147 413 Ac-CQTWFCYW-[hLeu]-ENG-NH₂ 1412 414Ac-CQTWPCYW-[hLeu]-ENG-NH₂ 2735 415 Ac-CQTWNCYW-[hLeu]-ENG-NH₂ 1849 416Ac-CQTWRCYW-[hLeu]-ENG-NH₂ 278 417 Ac-CQTWTCYW-[hLeu]-ENG-NH₂ 114 418Ac-CQTWECYW-[hLeu]-ENG-NH₂ 164 419 Ac-CQTGQCYW-[hLeu]-ENG-NH₂ >10,000420 Ac-CQTPQCYW-[hLeu]-ENG-NH₂ >10,000 421Ac-CQTNQCYW-[hLeu]-ENG-NH₂ >10,000 422Ac-CQTRQCYW-[hLeu]-ENG-NH₂ >10,000 423Ac-CQTTQCYW-[hLeu]-ENG-NH₂ >10,000 424Ac-CQTEQCYW-[hLeu]-ENG-NH₂ >10,000 425 Ac-CQFWQCYW-[hLeu]-ENG-NH₂ 1152426 Ac-CQPWQCYW-[hLeu]-ENG-NH₂ >10,000 427 Ac-CQNWQCYW-[hLeu]-ENG-NH₂336 428 Ac-CQRWQCYW-[hLeu]-ENG-NH₂ 469 429 Ac-CQEWQCYW-[hLeu]-ENG-NH₂773 450 Ac-CFTWQCYW-[hLeu]-ENG-NH₂ 205 451 Ac-CPTWQCYW-[hLeu]-ENG-NH₂27412 452 Ac-CNTWQCYW-[hLeu]-ENG-NH₂ 61 453 Ac-CGTWQCYW-[hLeu]-ENG-NH₂167 454 Ac-CTTWQCYW-[hLeu]-ENG-NH₂ 59 28 10 455Ac-CETWQCYW-[hLeu]-ENG-NH₂ 101 456 Ac-CQTWQCYW-[N-MeLeu]-ENG-NH₂ >6000457 Ac-CQTWQCYW-[α-MeOrn]-ENG-NH₂ 46 64 12 458Ac-CQTWQCYW-[α-MeOrn]-ENG-NH₂ 28 31 7 459Ac-CQTWQC-[α-MePhe]-W-[hLeu]-ENG-NH₂ ~30000 460Ac-CQTWQCYW-[Aib]-ENG-NH₂ 31 34 12 461 Ac-CQTWQC-[hTyr]-W-[hLeu]-ENG-NH₂~6000 462 Ac-CQTWQC-[Bip]-W-[hLeu]-ENG-NH₂ 237 463Ac-CQTWQCYW-[Ogl]-ENG-NH₂ 66 163 76 464Ac-CQTWQCYW-[hLeu]-[Lys(Ac)]-NG-NH₂ 19 32 3 465Ac-CQTWQCYW-[hLeu]-ENGG-NH₂ 61 140 24 466 Ac-CQTWQCYW-[hLeu]-ENGP-NH₂ 97467 Ac-CQTWQCYW-[hLeu]-ENGE-NH₂ 180 468Ac-CQTWQCYW-[hLeu]-ENG-(D)Glu-NH₂ 183 469Ac-CQTWQCY-[α-MePhe]-[hLeu]-ENG-NH₂ ~30000 470Ac-CQTWQCYW-[hLeu]-ENGP-NH₂ 239 471 Ac-CQTWQCYW-[hLeu]-ENGG-NH₂ 362 472Ac-CQTWQCYW-[hLeu]-ENGL-NH₂ 174 473 Ac-CQTWQCYW-[hLeu]-ENGF-NH₂ 131 474Ac-CQTWQCYW-[hLeu]-ENGE-NH₂ 129 475 Ac-CQTWQCYW-[hLeu]-ENGN-NH₂ 66 23476 Ac-CQTWQCYW-[hLeu]-ENGT-NH₂ 160 477Ac-CQTWQCYW-[hLeu]-ENGR-NH₂ >10,000 >1000 478Ac-PCQTWQCYW-[hLeu]-ENG-NH₂ 97 479 Ac-LCQTWQCYW-[hLeu]-ENG-NH₂ 61 26 21480 Ac-FCQTWQCYW-[hLeu]-ENG-NH₂ 56 25 16 481 Ac-ECQTWQCYW-[hLeu]-ENG-NH₂482 Ac-NCQTWQCYW-[hLeu]-ENG-NH₂ 483 Ac-RCQTWQCYW-[hLeu]-ENG-NH₂ 484Ac-CQTWQCY-[2-Nal]-[hLeu]-ENG-NH₂ 485 Ac-CQTWQCY-[1-Nal]-[hLeu]-ENG-NH₂18 37 6 486 Ac-CQTWQC-[2-Nal]-W-[hLeu]-ENG-NH2 48 73 11 487Ac-CQTWQC-[1-Nal]-[2-Nal]-[hLeu]-ENG-NH₂ 78 125 17 488Ac-CQTWQC-[2-Nal]-[1-Nal]-[hLeu]-ENG-NH₂ 117 489Ac-CQTWQC-[Aic]-W-[hLeu]-ENG-NH₂ 126 490 Ac-CQTWQCHW-[hLeu]-ENG-NH₂~6000 491 Ac-CQTWQCYH-[hLeu]-ENG-NH₂ 398 492Ac-CQTWQC-[Tyr(OMe)]-W-[hLeu]-ENG-NH₂ ~30000 493Ac-CQTWQCY-[Bip]-[hLeu]-ENG-NH₂ 42 51 11 494Ac-CQTWQCY-[Tyr(OMe)]-[hLeu]-ENG-NH₂ 998 495 Ac-CQTWQCHH-[hLeu]-ENG-NH₂148 496 Ac-CQTWQCY-[α-MeTrp]-[hLeu]-EQG-NH₂ >30000 497Ac-CQTW-[(K(PEG8)]-CYWLENG-NH₂ 212 498 Ac-CQTWQCYWX-LNG-NH₂ 800 499Ac-CQTW-[K(PEG8)]CYW-[K(PEG8)]-ENG-NH₂ 753 500Ac-CQTW-[K(Palm)]-CYWLENG-NH₂ ~30000 501Ac-CQTWQCYW-[Orn]-[K(Palm)]-NG-NH₂ >6000 502Ac-Gly-[(D)Asn]-(D)Glu-(D)Leu-(D)Trp-(D)Tyr-(D)Cys- >30000(D)Gln-(D)Trp-(D)Thr-(D)Gln-(D)Cys-NH₂ 503Ac-CQTWQCYW-[(Orn)]-[K(Peg8)]-NG-NH₂ 169 504 Ac-CRTWQCYWHEFG-NH₂ 166 505Ac-CRTWECYWHTFG-NH₂ 333 506 Ac-CQTWQCYWHEFG-NH₂ 169 507Ac-CQTWQCYWRNFGDS-NH₂ 96 508 Ac-CQTWQCYWRNFESG-NH₂ 315 509Ac-CQDWQCYWREFGPG-NH₂ 82 510 Ac-CQDWQCYWRSFGPQ-NH₂ 117 511Ac-CQTWQCYWRTLGPSNH2 66 512 Ac-CQTWQCYW-[(D)Pro]-ENG-NH₂ >30000 513Ac-CQTWQCYWELNG-NH₂ 79 514 Ac-CQTWECYWELNG-NH₂ 154 515Ac-CQTWQCY[(1-Nal]-[α-MeLeu]-ENG-NH₂ 22 67 13 516Ac-CQTWQCY-[1-Nal]-[(D)Asn]-ENG-NH₂ 145 98 517Ac-CQTWQCYWLE-[K(Palm)]-G-NH₂ >6000 518 Ac-CQTWQCYWLEN-[K(Palm)]-NH₂2800 519 Ac-CSTWECYWRTFG-NH₂ 252 520 Ac-CDSWECYWRTYG-NH₂ 366 521Ac-CSTWECYWHTYG-NH₂ 181 286 97

TABLE 4A IC50 of Illustrative examples of dimers of Peptides Containingthe Ac-[Pen]-XXWX- [Pen]-XXXX Motif and analogues Human Rat pStat3 SEQID ELISA ELISA HTRF NO. Sequence (nM) (nM) (nM) 522[Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]- ** * ENG-NH₂]₂ DIG523 [Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]- * ** ENG-NH₂]₂PEG25 524 [Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α- ** **Me-Leu]-QNN-NH₂]₂ DIG 525[Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α- * **Me-Leu]-QNN-NH₂]₂ PEG25 526[Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]- *** ***[Aib]-[Lys(Ac)]-NQ-NH₂]₂ DIG 527[Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]- ** ***[Aib]-[Lys(Ac)]-NQ-NH2]₂ PEG25 528[Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeVal]- *[Lys(Ac)]-NN-[D)Lys]]₂ DIG 529[Ac-[Pen]-QTWQ[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2- *Nal]-[α-MeVal]-[Lys(Ac)]-NN-[D)Lys]]₂ DIG 530[Ac-[Pen]-QTWQ[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2- ** *Nal]-[α-MeVal]-KNN-NH₂]₂ DIG 531[Ac-[Pen]-QTWQ[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2- *** *Nal]-K-[Lys(Ac)]-NN-NH₂]₂ DIG 532[Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]- ** *[Lys(Ac)]-NN-NH₂]₂ DIG 533[Ac-[α-MeLys]-[Pen]-QTWQ-[Pen]-[Phe(4-CONH₂)]-[2-Nal]- ****[α-MeVal]-[Lys(Ac)]-NN-NH₂]₂ DIG 534[Ac-[Pen]-QTWQ-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[α-MeLys]- * ** *[Lys(Ac)]-NN-NH₂]₂ DIG 535[Ac-[Pen]-NTWQ-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[Aib]-KNN- * ** * NH₂]₂ DIG536 [Ac-[Pen]-NTWQ-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[4-amino-4- *carboxy-tetrahydropyran]-KNN-NH₂]₂ DIG 537[Ac-[Pen]-NTWQ-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[Achc]- * KNN-NH₂]₂ DIG 538[Ac-[Pen]-NTWQ-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[Acvc]- * ** * KNN-NH₂]₂ DIG539 [Ac-[Pen]-NTWQ-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[α-MeLeu]- * KNN-NH₂]₂DIG 540 [Ac-[Pen]-NTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Aib]-KNN- * NH₂]₂ DIG541 [Ac-[Pen]-NTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[4-amino-4- *carboxy-tetrahydropyran]-KNN-NH₂]₂ DIG 542[Ac-[Pen]-NTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Achc]-KNN- * NH₂]₂ DIG 543[Ac-[Pen]-NTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Acvc]-KNN- * NH₂]₂ DIG 544[Ac-[Pen]-NTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLeu]- * KNN-NH₂]₂ DIG 545[Ac-[Pen]-QTWQ-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[α-MeLys]- *[Lys(Ac)]-NN-NH₂]₂ IDA 546[Ac-[Pen]-QTWQ-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[α-MeLys]- *[Lys(Ac)]-NN-NH₂]₂ [IDA-βAla] * = <10 nM; ** = 10-25 nM *** = 25-100 nM,**** = 100-1000 nM, ***** = 1000-10,000 nM.

TABLE 4B IC50 of Illustrative Peptides Containing theAc-[Pen]-XXWX-[Pen]-XXXX Motif and Analogues Human Rat pStat3 SEQ IDELISA ELISA HTRF NO. Sequence (nM) (nM) (nM) 547Ac-[Pen]-RTWQ-[Pen]-YWRKFG-[AEA]-[(D)-Lys]-NH₂ **** **** *** 548Ac-A-[Pen]-DWV-[Pen]-YWRKFG-[AEA]-[(D)-Lys]-NH₂ >30000 549Ac-[[Pen]-QTWQ-[Pen]-YW-[hLeu]-ENG-NH₂ **** 550 Ac-[Pen]-QTWQ-[Pen]-YW[N-MeArg]-ENG-NH₂ >30000 551 Ac-[Pen]-QTWQ-[Pen]-YW-[hLeu]-ENG-NH₂ ****552 Ac-[Pen]-QTWQ-[Pen]-YW-[N-MeArg]-ENG-NH₂ >30000 553Ac-A-[Pen]-DWV-[Pen]-YW-[Orn]-[Dap]-FG-[AEA]-[(D)-Lys]- >30000 NH₂ 554Ac-[Pen]-QTWQ-[Pen]-YW-[α-MeLeu]-ENG-NH₂ *** **** ** 555Ac-[Pen]-QTWQ-[Pen]-YW-[(D)Asn]-ENG-NH₂ ***** 556Ac-[Pen]-QTWQ-[Pen]-Y-[2-Nal]-[α-MeLys]-ENG-NH₂ *** **** * 557Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-ENG- *** **** ** NH₂558 Ac-[Pen]-QTWQ-[Pen]-[2-Nal]-[2-Nal]-[α-MeLys]-ENG-NH₂ **** **** **559 Ac-[Pen]-QTWQ-[Pen]-Y-[2-Nal]-[α-MeOrn]-ENG-NH₂ *** **** ** 560Ac-[Pen]-QTWQ-[Pen]-YW-[α-MeOrn]-ENG-NH₂ **** **** *** 561Ac-[Pen]-QTWQ-[Pen]-Y-[1-Nal]-[α-MeOrn]-ENG-NH₂ **** **** *** 562Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeOrn]- **** ***[Lys(Ac)]-NG-NH₂ 563 Ac-[Pen]-QTWQ-[Pen]-YW-[α-MeLys]-[Lys(Ac)]-NG-NH₂**** *** 564 Ac-[Pen]-QTWQ-[Pen]-[Phe-(4-OMe)]-W-[α-MeLys]- *** *** **[Lys(Ac)]-NG-NH₂ 565 Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-*** *** * [Lys(Ac)]-NG-NH₂ 566Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[1-Nal]-[α-MeLys]- *** **** ***[Lys(Ac)]-NG-NH₂ 567Ac-[Pen]-QTWQ-[Pen]-[BIP]-[2-Nal]-[α-MeLys]-[Lys(Ac)]- >10,000  NG-NH₂568 Ac-[Pen]-QTWQ-[Pen]-Phe(3,4-Cl₂)-[2-Nal]-[α-MeLys]- ****[Lys(Ac)]-NG-NH₂ 569Ac-[Pen]-QTWQ-[Pen]-[Phe(3,5-F₂)]-[2-Nal]-[α-MeLys]- ****[Lys(Ac)]-NG-NH₂ 570 Ac-[Pen]-QTWQ-[Pen]-[Phe(4-NH₂)]-[2-Nal]-[α-MeLys]-**** [Lys(Ac)]-NG-NH₂ 571Ac-[Pen]-QTWQ-[Pen]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ >10000 572Ac-[Pen]-QTWQ[Pen]-[Phe(3,4-Cl₂)]-[2-Nal]-[α-MeOrn]-ENG- **** NH₂ 573Ac-[Pen]-QTWQ[Pen]-[Phe(4-CN)]-[2-Nal]-[α-MeOrn]-ENG- **** NH₂ 574Ac-[Pen]-QTWQ[Pen]-[Phe(3,5-F₂)]-[2-Nal]-[α-MeOrn]-ENG- **** NH₂ 575Ac-[Pen]-QTWQ[Pen]-[Phe(4-CH₂CO₂H)]-[2-Nal]-[α-MeOrn]- ENG-NH₂ 576Ac-[Pen]-QTWQ[Pen]-[Phe(4-CH₂COEt₂)]-[2-Nal]-[α-MeOrn]- ENG-NH₂ 577Ac-[Pen]-QTWQ[Pen]-[Phe(penta-F)]-[2-Nal]-[α-MeOrn]-ENG- NH₂ 578Ac-[Pen]-QTWQ[Pen]-[Phe(4-CF₃)]-[2-Nal]-[α-MeLys]-ENG- NH₂ 579Ac-[Pen]-QTWQ[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α- MeLys]-ENG-NH₂580 Ac-[Pen]-QTWQ[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]-ENG-NH₂ 581 Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-**** K(ivDde)-NG-NH2 582 succinicacid-[Pen]-QTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[α- *** *** *MeLys]-[Lys(Ac)]-NG-NH₂ 583 glutaricacid-[Pen]-QTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[α- *** *** **MeLys]-[Lys(Ac)]-NG-NH₂ 5844-methylmorpholine-2,6-dione-[Pen]-QTWQ[Pen]-[Phe(4- *** *** **OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ 585 pyroglutamicacid-[Pen]-QTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[α- *** *** *MeLys]-[Lys(Ac)]-NG-NH₂ 586 isovalericacid-[Pen]-QTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[α- *** *** **MeLys]-[Lys(Ac)]-NG-NH₂ 587 gallicacid-[Pen]-QTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[α- *****MeLys]-[Lys(Ac)]-NG-NH₂ 588 octanoicacid-[Pen]-QTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[α- ****MeLys]--[Lys(Ac)]-NG-NH₂ 589 4-Biphenylaceticacid-[Pen]-QTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-- ****[α-MeLys]-[Lys(Ac)]-NG-NH₂ 590 4-fluorophenylaceticacid-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2- *** **** *Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ 591 Hy-[Pen]-ADWV-[Pen]-YWHTFG-NH₂ >6000 592 Ac-[Pen]-GTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α- ** *MeLys]-ENG-NH₂ 593Ac-[Pen]-TTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α- ** *MeLys]-ENG-NH₂ 594Ac-[Pen]-STWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α- ** *MeLys]-ENG-NH₂ 595Ac-[Pen]-[Dap]-TWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]- * *** *[α-MeLys]-ENG-NH₂ 596Ac-[Pen]-[α-MeOrn]-TWQ[Pen]-[Phe[4-(2-aminoethoxy)]-[2- ****Nal]-[α-MeLys]-ENG-NH₂ 597Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α- * *MeLys]-ENG-NH2 598Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α- * *** *MeLys]-[Lys(Ac)]-NG-NH₂ 599Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α- * ** *MeLys]-[Lys(Ac)]-NN-NH₂ 600Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α- ** *MeLys]-ENG-NH₂ 601Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α- * *** *MeLys]-ENA-NH₂ 602Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α- * * *MeLeu]-[Lys(Ac)]-NN-NH₂ 603Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α- * * *MeLeu]-QNN-NH₂ 604Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]- * * ENN-NH₂605 Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-Aib- * *[Lys(Ac)]-NN-NH₂ 606Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]- * *[Lys(Ac)]-NQ-NH₂ 607Ac-[Pen]-Dap(Ac)TWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]- ** *[2-Nal]-[α-MeLys(Ac)]-ENG-NH₂ 608Ac-[Pen]-[α-MeOrn(Ac)]-TWQ-[Pen]-[Phe[4-(2- ****acetylaminoethoxy)]-[2-Nal]-[α-MeLys(Ac)]-ENG-NH₂ 609Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]- * *[α-MeLys(Ac)]-[Lys(Ac)]-NG-NH₂ 610Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]- * *[α-MeLys(Ac)]-[Lys(Ac)]-NN-NH₂ 611Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]- ** *[α-MeLys(Ac)]-ENG-NH₂ 612Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]- ** *[α-MeLys(Ac)]-ENA-NH₂ 613Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]- * *[α-MeLeu]-[Lys(Ac)]-NN-NH₂ 614Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]- * *[α-MeLeu]-QNN-NH₂ 615Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]- ** *[Aib]-ENN-NH₂ 616Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]- * *[Aib]-[Lys(Ac)]-NN-NH₂ 617Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]- * *[Aib]-[Lys(Ac)]-NQ-NH₂ 618Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Aib]-ENN-NH₂ * 619Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]- ** [hLeu]-ENA-NH₂620 Ac-[Pen]-TTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]- *[Lys(Ac)]-NN-NH₂ 621Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Aib]-[Lys(Ac)]- * NA-NH₂ 622Ac-[Pen]-TTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]- *[Lys(Ac)]-NQ-NH₂ 623Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Aib]-[Lys(Ac)]- * NQ-NH₂ 624Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]- *[Lys(Ac)]-NA-NH₂ 625Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Aib]-[Lys(Ac)]- * NN-NH₂ 626Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]- *[hLeu]-[Lys(Ac)]-N-[βAla]-NH₂ 627Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[hLeu]- *[Lys(Ac)]-N-[βAla]-NH₂ 628Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]- *[Lys(Ac)]-N-[βAla]-NH₂ 629Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Aib]-[Lys(Ac)]- * N-βAla]-NH₂630 Ac-[Pen]-NTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Aib]-ENN-NH₂ * 631Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]- * [hLeu]-ENA-NH₂632 Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]- * * *[Lys(Ac)]-NN-NH₂ 633Ac-[Pen]-NTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Aib]-[Lys(Ac)]- * N-[βAla]-NH₂634 Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]- *[Lys(Ac)]-NQ-NH₂ 635Ac-[Pen]-NTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Aib]-[Lys(Ac)]- * NA-NH₂ 636Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]- *[Lys(Ac)]-NA-NH₂ 637Ac-[Pen]-NTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Aib]-[Lys(Ac)]- * NN-NH₂ 638Ac-[Pen]-NTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Aib]-[Lys(Ac)]- * NQ-NH₂ 639Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]- ** *[Lys(Ac)]-N-[βAla]-NH₂ 640Ac-[Pen]-NTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[hLeu]- *[Lys(Ac)]-N-[βAla]-NH₂ 641Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]- *[hLeu]-[Lys(Ac)]-N-[βAla]-NH2 642Ac-E-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]- *[Aib]-[Lys(Ac)]-NN-NH₂ 643Ac-(D)Asp-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2- *Nal]-[Aib]-[Lys(Ac)]-NN-NH₂ 644Ac-R-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]- *[Aib]-[Lys(Ac)]-NN-NH₂ 645Ac-(D)Arg-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2- *Nal]-[Aib]-[Lys(Ac)]-NN-NH₂ 646Ac-Phe-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]- *[Aib]-[Lys(Ac)]-NN-NH₂ 647Ac-(D)Phe-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2- *Nal]-[Aib]-[Lys(Ac)]-NN-NH₂ 648Ac-[2-Nal]-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2- *Nal]-[Aib]-[Lys(Ac)]-NN-NH₂ 649Ac-T-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]- *[Aib]-[Lys(Ac)]-NN-NH₂ 650Ac-L-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]- *[Aib]-[Lys(Ac)]-NN-NH₂ 651Ac-(D)Gln-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys(Ac)]-NN-NH₂ 652Ac-[(D)Asn]-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys(Ac)]-NN-NH₂ 653Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeVal]- *[Lys(Ac)]-NN-[(D)Lys]-NH₂ 654Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]- *[α-MeVal]-KNN-NH₂ 655Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]- ***K-[Lys(Ac)]-NN-NH₂ 666Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]- * [Lys(Ac)]-NN-NH₂667 Ac-[(D)Lys]-[Pen]-QTWQ-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[α- *****MeVal]-[Lys(Ac)]-NN-NH₂ 668Ac-[Pen]-QTWQ-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[α-MeLys]- *** *[Lys(Ac)]-NN-NH₂ 669Ac-[Pen]-QTWQ-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[α-MeVal]- ** *[Lys(Ac)]-NN-NH₂ 670Ac-[Pen]-QTWQ[Pen]-[Phe(4-CONH₂)]-[Phe(3,4-OMe₂)]-[α- **MeVal]-[Lys(Ac)]-NN-NH₂ 671Ac-[(D)Phe]-[Pen]-NTWQ[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys(Ac)]-NN-NH₂ 672Ac-[(D)Phe]-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-[Lys(Ac)]-NN-NH₂ 673Ac-[(D)Phe]-[Pen]-NTWQ[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Achc]-[Lys(Ac)]-NN-NH₂ 674Ac-[(D)Phe]-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-[Cit]-NN-NH₂ 675Ac-[(D)Phe]-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Achc]-[Cit]-NN-NH₂ 676Ac-[(D)Phe]-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys(Ac)]-N-[βAla]-NH₂ 677Ac-[(D)Phe]-[Pen]-NTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-[Lys(Ac)]-NN-NH₂ 678Ac-[(D)Phe]-[Pen]-NTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Achc]-[Lys(Ac)]-NN-NH₂ 679Ac-[(D)Phe]-[Pen]-NTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-[Cit]-NN-NH₂ 680Ac-[(D)Phe]-[Pen]-NTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Achc]- [Cit]-NN-NH₂681 Ac-[(D)Phe]-[Pen]-NTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Achc]- ENN-NH₂682 Ac-[Pen]-NTWQ[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[Aib]- [Lys(Ac)]-NN-NH₂683 Ac-[Pen]-NTWQ[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-Lys(Ac)]-NN-NH₂ 684Ac-[Pen]-NTWQ[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[Achc]- [Lys(Ac)]-NN-NH2 685Ac-[Pen]-NTWQ[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[Acpc]- [Lys(Ac)]-NN-NH₂ 686Ac-[Pen]-NTWQ[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[α-MeLeu]- [Lys(Ac)]-NN-NH₂687 Ac-[Pen]-NTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[Aib]-[Lys(Ac)]- NN-NH₂ 688Ac-[Pen]-NTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-[Lys(Ac)]-NN-NH₂ 689Ac-[Pen]-NTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[Achc]-[Lys(Ac)]- NN-NH₂ 730Ac-[Pen]-NTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[Acpc]-[Lys(Ac)]- NN-NH₂ 731Ac-[Pen]-NTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLeu]- [Lys(Ac)]-NN-NH₂ *= <10 nM; ** = 10-25 nM *** = 25-100 nM, **** = 100-1000 nM, *****= 1000-10,000 nM.

TABLE 5A IC50 of Illustrative Peptide Inhibitors (Thioethers) SEQ HumanID ELISA NO. Sequence/Structure (nM) 732

~6000 733

>30000 734

>30000 735

~6000 736

~3000 737

>30000 738

>30000 739

~6000 740

>6000 741

~30000 742

~6000 743

~6000 744

~30000 745

>6000 746

>6000 747

>6000 748

>6000 749

~30000 690

>30000 691

>30000

TABLE 5B IC50 of Illustrative Peptide Inhibitors (Thioethers)

Ac-Cyclo-[[Abu]-XXWXC]-[Phe(4-OMe)]-[2-Nal]-XXX—NH₂ SEQ Human Rat pStat3ID ELISA ELISA HTRF NO. Sequence (nM) (nM) (nM 692Ac-Cyclo-[[Abu]RTWQC]-YWRKFG- *** **** *** [AEA]-[(D)Lys]-NH₂ 693Ac-Cyclo-[CRTWQ-[Abu]]-YWRKFG- **** **** *** [AEA]-[(D)Lys]-NH₂ 694Ac-Cyclo-[[Abu]-QTWQC]-YWRENG- **** **** *** [AEA]-[(D)Lys]-NH₂ 695Ac-Cyclo-[[Abu]-RTWQ-[Pen]]- ***** YWRKFG-[AEA]-[(D)Lys]-NH₂ 696Ac-Cyclo-[[Pen]-RTWQ-[Abu]]- **** YWRKFG-[AEA]-[(D) Lys]-NH2 697Ac-Cyclo-[[(D)Cys]-RTWQ-[Abu]]- **** YWRKFG-[AEA]-[(D)-Lys]-NH₂ 698Ac-Cyclo-[[Abu]-QTWQC]-YW-[Orn]- **** [Dap]-NG-[AEA]-[(D) Lys]-NH₂ 699Ac-Cyclo-[[Abu]-QTWQC]-YW-[hLeu]- *** ** ENG-NH₂ 700Ac-Cyclo-[Abu]-QTWQ-(D)Cys]]-YW- ***** [hLeu]-ENG-NH₂ 701Ac-Cyclo-[[Abu]-QTWQ-[Pen]]-YW- ***** [hLeu]-ENG-NH₂ 702Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- *** **** *OMe)]-[2-Nal]-[α-MeLys]-ENG-NH₂ 703 Ac-Cyclo-[[Abu]-QTWQC]-YW-[α- ***** * MeLeu]-ENG-NH₂ 704 Ac-Cyclo-[[Abu]-QTWQC]-Y-[2-Nal]- ** ** *[α-MeLys]-ENG-NH₂ 705 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- ** ** *OMe)]-[2-Nal]-[α-MeLys]-ENG-NH₂ 706 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- ***** * OMe)]-[2-Nal]-[α-MeOrn]-ENG-NH₂ 707 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-*** *** * OMe)]-W-[α-MeOrn]-ENG-NH₂ 708 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-** *** * OMe)]-[2-Nal]-[α-MeLys]-ENG-NH₂ 709Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- ** ** **OMe)]-W-[α-MeLys]-[Lys(Ac)]-NG-NH₂ 710 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- ***** ** OMe)]-W-[α-MeLys]-ENG-NH₂ 711 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- ****** ** OMe)]-[1-Nal]-[α-MeLys]-[Lys(Ac)]- NG-NH₂ 712Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- * ** * OMe)]-[1-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ 713 Ac-Cyclo-[[Abu]-QTWQC]-YW-[α- *** *** **MeOrn]-[Lys(Ac)]-NG-NH₂ 714 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- *** **** ***OMe)]-[2-Nal]-[(D)Asn]-[Lys(Ac)]-NG- NH₂ 715Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- ****Phenoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]- NG-NH₂ 716Ac-Cyclo-[[Abu]-QTWQC]-[hPhe(3,4- ***** dimethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ 717 Ac-Cyclo-[[Abu]-QTWQC]-[DMT]-[2- *****Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ 718 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- **** * CONH₂)]-[2-Nal]-[α-MeLys]- [Lys(Ac)]NG-NH₂ 719Ac-Cyclo-[[Abu]-QTWQC]-Phe(3,4- **** ***Cl₂)[2-Nal]-[α-MeLys]-[Lys(Ac)]NG- NH₂ 720Ac-Cyclo-[[Abu]-QTWQ-[Pen]]-[Phe(4- **** **** ***OMe)]-[2-Nal]-[α-MeLys]-ENG-NH₂ 721 Ac-Cyclo-[[Abu]-QTWQ-[Pen]]-[Phe(4-*** **** *** OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]NG- NH₂ 722Ac-Cyclo-[[Pen]-QTWQ-[Abu]]-[Phe(4- OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]NG-NH₂ 723 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- >10,000OMe)]-[Trp(2,5,7-tri-tert-Butyl)]-[α- MeLys]-ENG-NH₂ 724Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- **** OMe)]-[Phe(4-Oallyl)]-[α-MeLys]-ENG-NH₂ 725 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- *** **** **OMe)]-[Tyr(3-tBu)]-[α-MeLys]-ENG- NH₂ 726 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-***** OMe)]-[Phe(4-tBu)]-[α-MeLys]-ENG- NH₂ 727Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- **** OMe)]-[Phe(4-guanidino)]-[α-MeLys]-ENG-NH₂ 728 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- ****OMe)]-[Phe(Bzl)]-[α-MeLys]-ENG-NH₂ 729Ac-Cyclo-[[Abu]-QTWQC]-[Tyr(3-tBu)]- >10,000 W-[α-MeLys]-ENG-NH₂ 780Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-tBu)]- ***** W-[α-MeLys]-ENG-NH₂ 781Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- *** *** ***guanidino)]-W-[α-MeLys]-ENG-NH₂ 782 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- **** * aminoethoxy)]-W-[α-MeLys]-ENG-NH₂ 783Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- **** CO₂H)]-W-[α-MeLys]-ENG-NH₂ 784Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- *** *** ** phenoxy)]-W-[α-MeLys]-ENG-NH₂785 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-CN)]- *** *** W-[α-MeLys]-ENG-NH₂ 786Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-Br)]- *** *** *** W-[α-MeLys]-ENG-NH₂ 787Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- *** *** * NH₂)]-W-[α-MeLys]-ENG-NH₂ 788Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- **** OMe)]-Phe(4-Me)-[α-MeLys]-ENG-NH₂789 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- *** *** **OMe)]-[1-Nal]-[α-MeLys]-ENG-NH₂ 790 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- **** * OMe)]-[2-Nal]-[α-MeOrn]-[Lys(Ac)]- NG-NH₂ 791Ac-Cyclo-[[Abu]-QTWQC]-[2-Nal]-[2- *** **** *Nal]-[α-MeOrn]-[Lys(Ac)]-NG-NH₂ 792 Ac-Cyclo-[[Abu]-QTWQC]-[Bip]-[2-**** Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ 793Ac-Cyclo-[[Abu]-QTWQC]-Cha-[2-Nal]- ***** [α-MeLys]-[Lys(Ac)]-NG-NH₂ 794Ac-Cyclo-[[Abu]-QTWQC]-[2-Nal]-[2- *** *** **Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ 795 Ac-Cyclo-[[Abu]-QTWQC]-[4- ****Pyridylalanine]-[2-Nal]-[α-MeLys]- [Lys(Ac)]-NG-NH₂ 796Ac-Cyclo-[[Abu]-QTWQC]-[β- ~10000 homoTyr]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ 797 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- ** ** *CONH₂)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]- NG-NH₂ 798Ac-Cyclo-[[Abu]-QTWQC]-[2-Nal]-[2- *** *** Nal]-[α-MeLys]-ENG-NH₂ 799Ac-Cyclo-[[Abu]-QT-[2-Nal]-QC]- **** [Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ 800 Ac-Cyclo-[[Abu]-QT-[1-Nal]-QC]- ****[Phe(4-OMe)]-[2-Nal]-[α-MeLys]- [Lys(Ac)]-NG-NH₂ 801Ac-Cyclo-[[Abu]-QTYQC]-[Phe(4- ~10000 OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ 802 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]- NG-NH₂ 803Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- *** OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NGGE-NH₂ 804 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]- NGAE-NH₂ 805Ac-Cyclo-[[Abu]-STWQC]-[Phe(4- OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NGGE-NH₂ 806 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-W-[α-MeLys]-[Lys(Ac)]-NGGE- NH₂ 807Ac-Cyclo-[[Abu]-QTWQC]-Y-[2-Nal]- [α-MeLys]-[Lys(Ac)]-NGGE-NH₂ 808Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- ** ** *OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NS- NH₂ 809Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- * ** * OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NA-NH₂ 810 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- ** *** *OMe)]-[2-Nal]-[Aib]-[Lys(Ac)]-NG-NH₂ 811Ac-Cyclo-[[Abu]-QTWQC]-[Phe-4-N₃]- *** *** **[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ 812 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-*** *** * OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]- QG-NH₂ 813Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-[Cit]-G-NH₂ 814 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- *** *** *OMe)]-[2-Nal]-[α-MeLys]-VNG-NH₂ 815 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- ****OMe)]-[2-Nal]-[Orn]-[Lys(Ac)]-NG-NH₂ 816 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-**** OMe)]-[2-Nal]-[Orn]-[Dap]-NG-NH₂ 817 Ac-Cyclo-[[Abu]-NTWQC]-[Phe(4-** *** * OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]- NG-NH₂ 818Ac-Cyclo-[[Abu]-QT-[Bip]-QC]-[Phe(4- ~10000OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]- NG-NH₂ 819Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- *** *** *OMe)]-[2-Nal]-[Cha]-[Lys(Ac)]-NG-NH₂ 820 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-*** OMe)]-[2-Nal]-[Chg]-[Lys(Ac)]-NG-NH₂ 821Ac-Cyclo-[[Abu]-QT-[Octgly]-QC]- >10000 [Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ 822 Ac-Cyclo-[[Abu]-QTWQC]-[Octgly]-[2- ~10000Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ 823 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-~10000 OMe)]-[Octgly]-[α-MeLys]-[Lys(Ac)]- NG-NH₂ 824Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- *** *** *OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]- NGE-NH₂ 825Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- * ** * OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NAE-NH₂ 826 Ac-Cyclo-[[Abu]-STWQC]-[Phe(4- *** *** ***OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]- NGE-NH₂ 827Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- **** OMe)]-W-[α-MeLys]-[Lys(Ac)]-NGE- NH₂828 Ac-Cyclo-[[Abu]-QTWQC]-Y-[2-Nal]- *** [α-MeLys]-[Lys(Ac)]-NGE-NH₂829 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * *aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENG- NH₂ 830Ac-Cyclo-[[Abu]-QTQQC]-[Phe[4-(2- >3000aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENG- NH₂ 831Ac-Cyclo-[[Abu]-QTHQC]-[Phe[4-(2- >3000aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENG- NH₂ 832Ac-Cyclo-[[Abu]-QT-[hPhe]-QC]-[Phe[4- >3000(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]- ENG-NH₂ 833Ac-Cyclo-[[Abu]-QT-[Glu(Bzl)]-QC]- >3000[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α- MeLys]-ENG-NH₂ 834Ac-Cyclo-[[Abu]-QT-[Bip]-QC]-[Phe[4- >3000(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]- ENG-NH₂ 835Ac-Cyclo-[[Abu]-QT-[Tic]-QC]-[Phe[4- >3000(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]- ENG-NH₂ 836Ac-Cyclo-[[Abu]-QT-[Phe[4-(2- >3000 aminoethoxy)]]-QC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENG- NH₂ 837Ac-Cyclo-[[Abu]-QT-[Phe(3,4-Cl2)]- >3000QC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- [α-MeLys]-ENG-NH₂ 838Ac-Cyclo-[[Abu]-QT-[Phe(4-OMe)]-QC]- >3000[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α- MeLys]-ENG-NH₂ 839Ac-Cyclo-[[Abu]-QT-[Orn(Benzyl)]-QC]- >3000[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α- MeLys]-ENG-NH₂ 840Ac-Cyclo-[[Abu]-QT- [Orn(Benzaldehyde)]-QC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENG- NH₂ 841 Ac-Cyclo-[[Abu]-QTWQC]-[PheOCH2CH2NHAc]-[2-Nal]-[α- MeLys]-ENG-NH₂ 842Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- aminoethoxy)]]-[2-Nal]-[α-MeLeu]-ENG-NH₂ 843 Ac-Cyclo-[[Abu]-QT-[5-hydroxyTrp]- ~3000QC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- [α-MeLys]-ENG-NH₂ 844Ac-Cyclo-[[Abu]-QT-[6-chloroTrp]-QC]- ** ** *[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α- MeLys]-ENG-NH₂ 845Ac-Cyclo-[[Abu]-QT-[N-MeTrp]-QC]- >3000[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α- MeLys]-ENG-NH₂ 846Ac-Cyclo-[[Abu]-QT-[1,2,3,4-tetrahydro- **** norharman]-QC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENG- NH₂ 847Ac-Cyclo-[[Abu]-QT-[Phe(4-CO2H)]- >3000QC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- [α-MeLys]-ENG-NH₂ 848Ac-Cyclo-[[Abu]-QT-[Phe(4-CONH2)]- >3000QC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- [α-MeLys]-ENG-NH₂ 849Ac-Cyclo-[[Abu]-QT-[Phe(4-CONH2)]- >3000QC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- [α-MeLys]-ENG-NH₂ 850Ac-Cyclo-[[Abu]-QT-[Phe(3,4-OMe)]- ~3000QC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- [α-MeLys]-ENG-NH₂ 851Ac-Cyclo-[[Abu]-QT-[α-MePhe]-QC]- ****[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α- MeLys]-ENG-NH₂ 852Ac-Cyclo-[[Abu]-QT-[Phe(4-CF3)]-QC]- ~3000[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α- MeLys]-ENG-NH₂ 853Ac-Cyclo-[[Abu]-QT-[Phe(4-tBu)]-QC]- >3000[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α- MeLys]-ENG-NH₂ 854Ac-Cyclo-[[Abu]-QT-[Phe(2,4-Me2)]- ****QC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- [α-MeLys]-ENG-NH₂ 855Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * ** *aminoethoxy)]]-[2-Nal]-[α-MeLys]- DNG-NH₂ 856Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * aminoethoxy)]]-[2-Nal]-[α-MeLys]-QNG-NH₂ 857 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * *aminoethoxy)]]-[2-Nal]-[α-MeLys]- [Lys(Benzoic acid)]-NG-NH₂ 858Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * ** *aminoethoxy)]]-[2-Nal]-[α-MeLys]- [Lys(succinic acid)]-NG-NH₂ 859Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Lys(glutaric acid)]-NG-NH₂ 860 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * *aminoethoxy)]]-[2-Nal]-[α-MeLys]- [Lys(pyroglutamic acid)]-NG-NH₂ 861Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * ** *aminoethoxy)]]-[2-Nal]-[α-MeLys]- [Lys(isovaleric acid)]-NG-NH₂ 862Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- ~3000aminoethoxy)]]-[2-Nal]-[α-MeLys]- [Lys(Palm)]-NG-NH₂ 863Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- aminoethoxy)]]-[2-Nal]-[α-MeLys]-Lys[(PEG1)]-NG-NH₂ 864 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]- [Lys(PEG2)]-NG-NH₂ 865Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Dap(Benzoic acid)]-NG-NH₂ 866 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]- [Dap(succinic acid)]-NG-NH₂ 867Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Dap(glutaric acid)]-NG-NH₂ 868 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- ** *aminoethoxy)]]-[2-Nal]-[α-MeLys]- [Dap(pyroglutamic acid)]-NG-NH₂ 869Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- aminoethoxy)]]-[2-Nal]-[α-MeLys]-Dap(IVA)NG-NH₂ 870 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]- [Dap(PEG1)]-NG-NH₂ 871Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Dap(PEG2)]-NG-NH₂ 872 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- ** **aminoethoxy)]]-[2-Nal]-[α-MeLys]- [Dap(PEG2-Ac)]-NG-NH₂ 873Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Lys(Ac)]--NG-[AEA]-[(D)Lys]-NH₂ 874Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-[(D)Lys]-NH₂ 875 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * *aminoethoxy)]]-[2-Nal]-[α-MeLys]- [Lys(Ac)]-NG-[AEA]-NH₂ 876Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- ** *aminoethoxy)]]-[2-Nal]-[Aib]-[Lys(Ac)]- QG-NH₂ 877Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * ** *aminoethoxy)]]-[2-Nal]-[Aib]-QNG-NH₂ 878Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * *aminoethoxy)]]-[2-Nal]-[Aib]-ENG-NH₂ 879Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- *** **aminoethoxy)]]-1-Nal[Aib]-[Lys(Ac)]- NG-NH₂ 880Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * ** *aminoethoxy)]]-[2-Nal]-[Aib]-[Lys(Ac)]- NA-NH₂ 881Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * *aminoethoxy)]]-[2-Nal]-[Aib]-KNG-NH₂ 882Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- **** aminoethoxy)]]-[Phe(4-CO₂H)]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ 883 Ac-Cyclo-[[Abu]-[Dap]-TWQC]-[Phe[4- ****(2-aminoethoxy)]]-[Phe(4-Phenoxy)]-[α- MeLys]-[Lys(Ac)]-NG-NH₂ 884Ac-Cyclo-[[Abu]-DapTWQC]-[Phe[4-(2- **** aminoethoxy)]]-[Phe[4-(2-aminoethoxy)]]-[α-MeLys]-[Lys(Ac)]- NG-NH₂ 885Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- >3000aminoethoxy)]]-[α-MeLys]-[Lys(Ac)]- NG-NH₂ 886Ac-Cyclo-[[Abu]-DabTWQC]-[Phe[4-(2- >1000aminoethoxy)]]-[hPhe]-[α-MeLys]- [Lys(Ac)]-NG-NH₂ 887Ac-Cyclo-[[Abu]-DapTWQC]-[Phe[4-(2- >3000aminoethoxy)]]-[Glu(Bzl)]-[α-MeLys]- [Lys(Ac)]-NG-NH₂ 888Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- ** * aminoethoxy)]]-W-[α-Me-Orn]-ENG-NH₂ 889 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * *aminoethoxy)]]-W-[α-MeLys]-[Lys(Ac)]- NG-NH₂ 890Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- ** ** aminoethoxy)]]-W-[α-Me-Orn]-[Lys(Ac)]-NG-NH₂ 891 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * *aminoethoxy)]]-[2-Nal]-[α-Me-Orn]- [Lys(Ac)]-NG-NH₂ 892Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * *aminoethoxy)]]-[2-Nal]-[α-MeLys]- [Lys(Ac)]-NG-NH₂ 893Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- ** **aminoethoxy)]]-[2-Nal]-[Orn]-[Lys(Ac)]- NG-NH₂ 894Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- *** aminoethoxy)]]-W-[Orn]-ENG-NH₂ 895Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- ****aminoethoxy)]]-W-[Orn]-[Dap]-NG-NH₂ 896Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- ****aminoethoxy)]]-W-[Orn]-[Dap(Ac)]-NG- NH₂ 897Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- *** ***aminoethoxy)]]-[2-Nal]-[Orn]-[Dap]-NG- NH₂ 898Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- ***aminoethoxy)]]-[2-Nal]-[Orn]-[Dap(Ac)]- NG-NH₂ 899Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- ** * aminoethoxy)]]-W-[hLeu]-ENG-NH₂900 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * *(acetyl-aminoethoxy)]]-[2-Nal]-[α- MeLys(Ac)]-[Lys(Ac)]-NG-NH₂ 901Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * aminoethoxy)]]-W-[α-Me-Leu]-ENG-NH₂ 902 Succicinyl-Cyclo-[[Abu]-QTWQC]- * * *[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α- MeLys]-[Lys(Ac)]-NG-NH₂ 903Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- *****aminoethoxy)]]-W-[α-MeLys]-[Lys(Ac)]- [Dap]-G-NH₂ 904Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- *** *aminoethoxy)]]-W-[α-MeLys]-[Lys(Ac)]-[6-amino-1,4-diazepane-2,5-dione]-NH₂ 905Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- *** aminoethoxy)]]-W-Chg-[Lys(Ac)]-NG-NH₂ 906 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * *(acetyl-aminoethoxy)]]-[2-Nal]-[α- MeLys(Ac)]-ENG-NH₂ 907Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- **** aminoethoxy)]]-[Phe(4-CONH₂)]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ 908 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- ** *** *aminoethoxy)]]-[Phe(3,4-OMe₂]-[α- MeLys]-[Lys(Ac)]-NG-NH₂ 909Ac-Cyclo-[[Abu]-[Dap]-TWQC]-[Phe[4- >3000(2-aminoethoxy)]]-[Tic]-[α-MeLys]- [Lys(Ac)]-NG-NH₂ 910Ac-Cyclo-[[Abu]-DapTWQC]-[Phe[4-(2- ***aminoethoxy)]]-[Phe(3,4-Cl₂)]-[α- MeLys]--[Lys(Ac)]-NG-NH₂ 911Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * *aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENQ- NH₂ 912Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * *aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN- NH₂ 913Ac-Cyclo-[[Abu]-TTWQC]-[Phe[4-(2- * *aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENG- NH₂ 914Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * aminoethoxy)]]-[2-Nal]-[α-Me-Gly(Ethyl)]Lys(Ac)]-NG-NH₂ 915 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * *aminoethoxy)]]-[2-Nal]-[α-MeVal]- [Lys(Ac)]-NG-NH₂ 916Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * aminoethoxy)]]-[2-Nal]-[α-MeSer]-[Lys(Ac)]-NG-NH₂ 917 Ac-Cyclo-[[Abu]-QTDapQC]-[Phe[4-(2- >3000aminoethoxy)]]-[2-Nal]-[α-MeLys]- [Lys(Ac)]-NG-NH₂ 918Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- >3000 aminoethoxy)]]-[Dap]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ 919 Ac-Cyclo-[[Abu]-QTRQC]-[Phe[4-(2- >3000aminoethoxy)]]-[2-Nal]-[α-MeLys]- [Lys(Ac)]-NG-NH₂ 920Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- >3000aminoethoxy)]]-R-[α-MeLys]-[Lys(Ac)]- NG-NH₂ 921Ac-Cyclo-[[Abu]-QTDapQC]-[Phe[4-(2- >3000aminoethoxy)]]-[Dap]-[α-MeLys]- [Lys(Ac)]-NG-NH₂ 922Ac-Cyclo-[[Abu]-QTDQC]-[Phe[4-(2- >3000aminoethoxy)]]-[2-Nal]-[α-MeLys]- [Lys(Ac)]-NG-NH₂ 923Ac-Cyclo-[[Abu]-QTWQC]-|Phe[4-(2- >3000aminoethoxy)]]-D-[α-MeLys]-[Lys(Ac)]- NG-NH₂ 924Ac-Cyclo-[[Abu]-QTDQC]-[Phe[4-(2- >3000aminoethoxy)]]-D-[α-MeLys]-[Lys(Ac)]- NG-NH₂ 925Ac-(D)Lys-[Cyclo-[[Abu]-QTWQC]]- * ** *[Phe(4-OMe)]-[2-Nal]-[α-MeLeu]-ENG- NH₂ 926Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- ** *aminoethoxy)]]-[2-Nal]-[α-MeLys]-RNG- NH₂ 927Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Orn]-NG-NH₂ 928 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * *aminoethoxy)]]-[2-Nal]-[α-MeLys]- KNG-NH₂ 929Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * aminoethoxy)]]-[2-Nal]-[α-MeLys]-hRNG-NH₂ 930 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * *aminoethoxy)]]-[2-Nal]-[hLeu]- [Lys(Ac)]-N-[βAla]-NH₂ 931Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- ** *aminoethoxy)]]-[2-Nal]-[Cit]-[Dap]-NG- NH₂ 932Ac-Cyclo-[[Abu]-[α-Me-Orn]-TWQC]- *** **[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α- MeLys]-ENG-NH₂ 933Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * aminoethoxy)]]-[2-Nal]-[α-MeLys]-NNG-NH₂ 934 Ac-Cyclo-[[Abu]-STWQC]-[Phe[4-(2- ****aminoethoxy)]]-[2-Nal]-[α-MeLys]- KNGGE-NH₂ 935Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * *(acetyl-aminoethoxy)]]-[2-Nal]-[α- MeLys(Ac)]-ENQ-NH₂ 936Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * *(acetyl-aminoethoxy)]]-[2-Nal]-[α- MeLys(Ac)]-ENN-NH₂ 937Ac-Cyclo-[[Abu]-TWQC]-[Phe[4-(2- aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENG-NH₂ 938 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-Me)]- * *[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ 939Ac-Cyclo-[[Abu]-QTWQC]-[Phe(3-Me)]- ** *[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ 940 Ac-Cyclo-[[Abu]-QTWQC]-[hTyr]-[2-***** Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ 941Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- ~3000aminoethoxy)]]-[α-MeTrp]-[α-MeLys]- [Lys(Ac)]-NG-NH₂ 942Ac-Cyclo-[[Abu]-[α-MeSer]-TWQC]- *** **[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α- MeLys]-[Lys(Ac)]-NG-NH₂ 943Ac-Cyclo-[[Abu]-Q-[α-MeSer]-WQC]- >3000[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α- MeLys]-[Lys(Ac)]-NG-NH₂ 944Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- >3000aminoethoxy)]]-[α-MePhe]-[α-MeLys]- [Lys(Ac)]-NG-NH₂ 945Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- ** * aminoethoxy)]]-W-[Aib]-ENG-NH₂946 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * *aminoethoxy)]]-[2-Nal]-[Aib]-[Lys(Ac)]- NG-NH₂ 947Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- ** * aminoethoxy)]]-[2-Nal]-[Aib]-E-[Dap(Ac)]-G-NH₂ 948 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * *aminoethoxy)]]-[2-Nal]-[Aib]-E- [Dab(Ac)]-G-NH₂ 949Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- ** * aminoethoxy)]]-[2-Nal]-[Aib]-E-[Lys(Ac)]-G-NH₂ 950 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- ** *aminoethoxy)]]-W-[Aib]-ENN-NH₂ 951Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * *aminoethoxy)]]-[2-Nal]-[α-MeLeu]-ENN- NH₂ 952Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- *** **aminoethoxy)]]-[Phe(3,4-OMe₂)]-[Aib]- ENG-NH₂ 953Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- *** *aminoethoxy)]]-[Phe(3,4-Cl₂)]-[Aib]- ENN-NH₂ 954Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * *aminoethoxy)]]-[2-Nal]-[α-MeLeu)-[Cit]- NN-NH₂ 955Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * *aminoethoxy)]]-[2-Nal]-[α-MeLeu]- [Lys(Ac)]-NN-NH₂ 956Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-Me)]- ** * [2-Nal]-[Aib]-ENG-NH₂ 957Ac-Cyclo-[[Abu]-QTWQC]-[Phe(3,4- *** ** F₂)]-[2-Nal]-[Aib]-ENG-NH₂ 958Ac-Cyclo-[[Abu]-QTWQC]-[Phe(3- **** CONH₂)]-[2-Nal]-[Aib]-ENG-NH₂ 959Ac-Cyclo-[[Abu]-QTWQC]-[Phe(2,4- **** Cl₂)]-[2-Nal]-[Aib]-ENG-NH₂ 960Ac-Cyclo-[[Abu]-QTWQC]-[Phe(3-Me)]- ** * [2-Nal]-[Aib]-ENG-NH₂ 961Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-Cl)]- ** * [2-Nal]-[Aib]-ENG-NH₂ 962Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-F)]- **** [2-Nal]-[Aib]-ENG-NH₂ 963Ac-Cyclo-[[Abu]-QTWQC]-[Phe(2,4-Cl₂ ***** 4-OBz)]-[2-Nal]-[Aib]-ENG-NH₂964 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4- *** ** OMe)]-[2-Nal]-[α-MeLeu]-ENG-[(D)Lys]-NH₂ 965 Ac-E-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * *aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN- NH₂ 966Ac-(D)Glu-[Cyclo-[[Abu]-QTWQC]- * * *[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α- MeLys]-ENN-NH₂ 967Ac-Arg-Cyclo-[[Abu]-QTWQC]-[Phe[4- * *(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]- ENN-NH₂ 968Ac-[(D)Arg]-Cyclo-[[Abu]-QTWQC]- * * *[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α- MeLys]-ENN-NH₂ 969Ac-F-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2- * * *aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN- NH₂ 970Ac-[(D)Phe]-Cyclo-[[Abu]-QTWQC]- * * *[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α- MeLys]-ENN-NH₂ 971Ac-[2-Nal]-Cyclo-[[Abu]-QTWQC]- * ** *[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α- MeLys]-ENN-NH₂ 972Ac-T-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * *aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN- NH₂ 973Ac-Leu-Cyclo-[[Abu]-QTWQC]-[Phe[4- * * *(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]- ENN-NH₂ 974Ac-[(D)Gln]-Cyclo-[[Abu]-QTWQC]- * * *[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α- MeLys]-ENN-NH₂ 975Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- ** aminoethoxy)]]-[2-Nal]-[Acpc]-ENN-NH₂ 976 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * *aminoethoxy)]]-[2-Nal]-[Acbc]-ENN- NH₂ 977Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * aminoethoxy)]]-[2-Nal]-[Achc]-ENN-NH₂ 978 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * *aminoethoxy)]]-[2-Nal]-[Acvc]-ENN-NH₂ 979Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * aminoethoxy)]]-[2-Nal]-[4-amino-4-carboxy-piperidine]-ENN-NH₂ 980 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * * *aminoethoxy)]]-[2-Nal]-[4-amino-4- carboxy-tetrahydropyran]-ENN-NH₂ 981Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * aminoethoxy)]]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NG-NH₂ 982 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- *aminoethoxy)]]-[2-Nal]-[α-MeLeu]-ENG- NH₂ 983Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- * aminoethoxy)]]-[2-Nal]-[α-MeLeu]-QNG-NH₂ 984 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- *aminoethoxy)]]-[2-Nal]-[α-MeLeu]-QN- [βAla]-NH₂ 985Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- *** aminoethoxy)]]-[2-Nal]-[α-MeLeu]-QDG-NH₂ 986 Ac-Cyclo-[[Abu]-QTWQC]- ****cyclo([Phe[4-(2-aminoethoxy)]]-[2-Nal]- [α-MeLeu]-QD]-G-NH₂ 987Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- *aminoethoxy)]]-[2-Nal]-[Aib]-QN-[βAla]- NH₂ 988Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- aminoethoxy)]]-[1,2,3,4-tetrahydro-norharman]-[Aib]-QNG-NH₂ 989 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- **aminoethoxy)]]-[5-hydroxyTrp]-[Aib]- QNG-NH₂ 990Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- *** aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-[Asn(isobutyl)]-G-N-NH₂ 991 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-*** aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-[Asp(1,4-diaminoethane)]-G- NH₂ 992Ac-(D)Phe-Cyclo-[[Abu]-QTWQC]- [Phe[4-(2-aminoethoxy)]]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN- NH₂ 993Ac-[(D)Arg]-Cyclo-[[Abu]-QTWQC]- [Phe[4-(2-aminoethoxy)]]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN- NH₂ * = <10 nM; ** = 10-25 nM ***= 25-100 nM, **** = 100-1000 nM, ***** = >1000 nM.

TABLE 5C IC50 of Illustrative Thioether Peptide Dimers Synthesized SEQHuman Rat pStat3 ID Linker ELISA ELISA HTRF NO. Moiety Sequence (nM)(nM) (nM) 994 DIG through [Ac-[(D)Lys]-Cyclo-[[Abu]- * *** * (D)LysQTWQC]-[Phe(4-OMe)]-[2- Nal]-[α-MeLeu]-ENG-NH₂]₂ DIG 995 DIG through[Ac-Cyclo-[[Abu]-QTWQC]- *** ** Phe[4-(2- [Phe[4-(2-aminoethoxy)]]-[2-aminoethoxy)] Nal]-[Aib]-QNG-NH₂]₂ DIG 996 DIG through[Ac-Cyclo-[[Abu]-QTWQC]- * ** * α-MeLys [Phe(4-OMe)]-[2-Nal]-[α-MeLys]-ENG-NH2]₂ DIG 997 PEG25 [Ac-[(D)Lys]-Cyclo-[[Abu]- * ** * throughα- QTWQC]-[Phe(4-OMe)]-[2- MeLys Nal]-[α-MeLys]-ENG-NH2]₂ PEG25 998 DIGthrough [Ac-Cyclo-[[Abu]-QTWQC]- * (D)Lys [Phe(4-OBzl)]-W-[α-MeLys]-ENG-NH₂]₂ DIG 999 PEG25 [Ac-Cyclo-[[Abu]-QTWQC]- * throughY(Bzl)-W-[α-MeLys]-ENG- (D)Lys NH₂]₂ PEG25 * = <10 nM; ** = 10-25 nM ***= 25-100 nM, **** = 100-1000 nM, ***** = >1000 nM

TABLE 6 IC50 of Peptide Inhibitors (Ring Closing Metathesis) Human SEQID ELISA NO. Sequence/Structure (nM) 1000

~20000 1001

~30000 1002

***** 1003

***** 1004

***** 1005

**** 1006

**** 1007

**** 1008

**** * = <10 nM; ** = 10-25 nM *** = 25-100 nM, **** = 100-1000 nM,***** = 1000-10,000 nM.

TABLE 7 IC50 of Illustrative Peptides Containing Cyclic amides (sidechain cyclizations)

Human SEQ ID ELISA NO. Sequence (nM) 1009Ac-Cyclo-[[Dap]-QTWQE]-YWRENG-[AEA]-[(D)Lys]-NH₂ ~6000 1010Ac-Cyclo-[EQTWQ-[Dab]]-YWRENG-[AEA]-[(D)Lys]-NH₂ >6000 1011Ac-Cyclo-[EQTWQ-[Dap]]-YWRENG-[AEA]-[(D)Lys]-NH₂ ~6000 1012Ac-Cyclo-[[Dab]QTWQE]-YWRENG-[AEA]-[(D)Lys]-NH₂ ~30000 1013Ac-Cyclo-[[Dap]-QTWQ-[(D)Asp]-YWRENG-[AEA]-[(D)Lys]-NH₂ >30000 1014Ac-Cyclo-[[Dap]-QTWQD]-YWRENG-[AEA]-[(D)Lys]-NH₂ >30000 1015Ac-Cyclo-[[DQTWQ-[Dab]]-YWRENG-[AEA]-[(D)Lys]-NH₂ ~6000 1016Ac-Cyclo-[[Dab]QTWQD]-YWRENG-[AEA]-[(D)Lys]-NH₂ >6000 1017Ac-Cyclo-[[(D)Dab]-QTWQ-[(D)Asp]]-YWRENG-[AEA]-[(D)Lys]- ~6000 NH₂ 1018Ac-Cyclo-[[(D)Asp]-QTWQ-[(D)Dab]]-YWRENG-[AEA]-[(D)Lys]- ~1400 NH₂ 1019Ac-Cyclo[[(D)Asp]-QTWQ-[(D)Dap]]-YWRENG-[AEA]-[(D)Lys]- ~30000 NH₂

TABLE 8 IC50 of Illustrative Peptides Containing the Ac-[Pen]-XXWXXXXXXMotif and Ac-XXXWX-[Pen]-XXXX analogues SEQ Human Rat pStat3 ID ELISAELISA HTRF NO. Sequence (nM) (nM) (nM) 1020 Ac-[Pen]-ADWVCYWHTFG-NH₂***** 1021 Ac-CADWV-[Pen]-YWHTFG-NH₂ ***** 1022Ac-[(D)Pen]-ADWVCYWHTFG-[AEA]-[(D)-Lys]-NH₂ **** ***** **** 1023Ac-CADWV-[(D)Pen]-YWHTFG-[AEA]-[(D)-Lys]-NH₂ >30000 ***** **** 1024Ac-[Pen]-RTWQCYWRKFG-[AEA]-[(D)-Lys]-NH₂ **** **** **** 1025Ac-ACDWV-[Pen]-YWRKFG-[AEA]-[(D)-Lys]-NH₂ ***** 1026Ac-A-[Pen]-DWVCYWRKFG-[AEA]-[(D)-Lys]-NH₂ **** 1027Ac-A-[hCys]-DWV-[Pen]-YWRKFG-[AEA]-[(D)-Lys]-NH₂ ~30000 1028Ac-CQTWQ-[Pen]-YW-[α-MeLeu]-ENG-NH₂ **** **** 1029Ac-CQTWQ-[Pen]-YW-[(D)Asn]-ENG-NH₂ ***** * = <10 nM; ** = 10-25 nM ***= 25-100 nM, **** = 100-1000 nM, ***** = 1000-10,000 nM.

SAR analysis of the activities of the peptide inhibitors testedindicated that the CXXXXC disulphide is associated with high activity.The two Trp residues and the Phe residue are also associated with highactivity, but it is recognized that these amino acids can be readilyexchanged with similar homologs (e.g., 1-Nal substituted for Trp and/orPhe substituted for Tyr). In addition, the data suggested that thepresence of one or more basic residues at the C-terminus is associatedwith high activity. Also, His-9 can be replaced by Arg or anotherhomolog and maintain or improve activity. The schematic below providesone illustrative consensus sequence (SEQ ID NO: 275) showing certainresidues associated with high activity.

Example 3 Stability of Peptide Inhibitors in Simulated Intestinal Fluid(SIF), Simulated Gastric Fluid (SGF) and Redox Conditions

Studies were carried out in simulated intestinal fluid (SIF) andsimulated gastric fluid (SGF) to evaluate gastric stability of thepeptide inhibitors of the present invention. In addition, studies werecarried out to assess redox stability of the peptide inhibitors of thepresent invention.

SIF was prepared by adding 6.8 g of monobasic potassium phosphate and10.0 g of pancreatin to 1.0 L of water. After dissolution, the pH wasadjusted to 6.8 using NaOH. DMSO stocks (2 mM) were first prepared forthe test compounds. Aliquots of the DMSO solutions were dosed into 6individual tubes, each containing 0.5 mL of SIF, which is pre-warmed to37° C. The final test compound concentration was 20 μM. The vials werekept in a benchtop Thermomixer® for the duration of the experiment. Ateach timepoint (0, 5, 10, 20, 40, 60, or 360 minutes or 24 hours), 1.0mL of acetonitrile containing 1% formic acid was added to one vial toterminate the reaction. Samples were stored at 4° C. until the end ofthe experiment. After the final timepoint is sampled, the tubes weremixed and then centrifuged at 3,000 rpm for 10 minutes. Aliquots of thesupernatant were removed, diluted 1:1 into distilled water containinginternal standard, and analyzed by LCMS/MS. Percent remaining at eachtimepoint was calculated based on the peak area response ratio of testto compound to internal standard. Time 0 was set to 100%, and all latertimepoints were calculated relative to time 0. Half-lives werecalculated by fitting to a first-order exponential decay equation usingGraphpad. Stability in SIF assays is shown in Tables 9 and 10.

SGF was prepared by adding 20 mg NaCl, 32 mg porcine pepsin (MPBiochemicals, catalog 02102599), and 70 μl HCl to 10 ml water (finalpH=2). Aliquots of SGF (0.5 ml each) were pre-warmed at 37° C. To startthe reaction, 1 μl of peptide stock solution (10 mM in DMSO) was addedto 0.5 ml SGF and thoroughly mixed such that the final peptideconcentration was 20 μM. The reactions were incubated at 37° C. withgentle shaking. At each time point (0, 15, 30, 60 min) 50 μl aliquotswere removed and added to 200 ul acetonitrile containing 0.1% formicacid to quench the reaction. Samples are stored at 4° C. until the endof the experiment and centrifuged at 10,000 rpm for 5 minutes. Aliquotsof the supernatant were removed, diluted 1:1 into distilled watercontaining internal standard, and analyzed by LCMS/MS. Percent remainingat each timepoint was calculated based on the peak area response ratioof test to compound to internal standard. Time 0 was set to 100%, andall later timepoints were calculated relative to time 0. Half-lives werecalculated by fitting to a first-order exponential decay equation usingGraphPad. Stability in SGF assays in shown in Tables 9 and 10.

TABLE 9 Stability of Illustrative Peptides containing theAc-[Pen]-XXWX-[Pen]-XXXX Motif and Analogues in Simulated IntestinalFluid (SIF) and Simulated Gastric Fluid (SGF) SGF SIF SEQ t½ t½ ID NO:Sequence (min) (min) 549 Ac-[[Pen]-QTWQ-[Pen]-YW-[hLeu]-ENG-NH₂ *****§1030 Ac-[Pen]-QTWQ-[Pen]-YWN-Me-RENG-NH₂ ****§ 551Ac-[Pen]-QTWQ-[Pen]-YW-[hLeu]-ENG-NH₂ *****§ 552Ac-[Pen]-QTWQ-[Pen]-YW-[N-MeArg]-ENG-NH₂ *** 554Ac-[Pen]-QTWQ-[Pen]-YW-[α-MeLeu]-ENG-NH₂ ** 1028Ac-CQTWQ-[Pen]-YW-[α-MeLeu]-ENG-NH₂ ***** 555Ac-[Pen]-QTWQ-[Pen]-YW-[(D)Asn]-ENG-NH₂ ** 1029Ac-CQTWQ-[Pen]-YW-[(D)Asn]-ENG-NH₂ ***** 556Ac-[Pen]-QTWQ-[Pen]-Y-[2-Nal]-[α-MeLys]-ENG-NH₂ ** 557Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-ENG-NH₂ *** ** 558Ac-[Pen]-QTWQ-[Pen]-[2-Nal]-[2-Nal]-[α-MeLys]-ENG-NH₂ ** 559Ac-[Pen]-QTWQ-[Pen]-Y-[2-Nal]-[α-MeOrn]-ENG-NH₂ ** 560Ac-[Pen]-QTWQ-[Pen]-YW-[α-MeOrn]-ENG-NH₂ ** 561Ac-[Pen]-QTWQ-[Pen]-Y-[1-Nal]-[α-MeOrn]-ENG-NH₂ ** 1031Ac-[Pen]-QTWQ-[Pen]-[[Phe(4-OMe)](OMe)]-[2-Nal]-[α-MeOrn]- *[Lys(Ac)]-NG-NH₂ 563Ac-[Pen]-QTWQ-[Pen]-YW-[α-MeLys]-[Lys(Ac)]-NG-NH₂ * * 1032Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-W-[α-MeLys]-[Lys(Ac)]-NG-NH₂ * 565Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG- * * NH₂566 Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[1-Nal]-[α-MeLys]-[Lys(Ac)]-NG- *NH₂ 1033 succinicanhydride-[Pen]-QTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]- ** *[Lys(Ac)]-NG-NH₂ 585 pyroglutamicacid-[Pen]-QTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]- ** *[Lys(Ac)]-NG-NH₂ 1034Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]- * *[Lys(Ac)]-NN-NH₂ 601Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLys]- * *ENA-NH₂ 602Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]- ** ***[Lys(Ac)]-NN-NH₂ 603Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]- * *QNN-NH₂ 604Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]-ENN- * * NH₂605 Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-Aib-[Lys(Ac)]-** *** NN-NH₂ 606Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]- * *[Lys(Ac)]-NQ-NH₂ 607Ac-[Pen]-Dap(Ac)TWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]-[α- * *MeLys(Ac)]-ENG-NH₂ 608Ac-[Pen]-[α-MeOrn(Ac)]-TWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2- ****** Nal]-[α-MeLys(Ac)]-ENG-NH₂ 609Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]-[α- * *MeLys(Ac)]-[Lys(Ac)]-NG-NH₂ 610Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]-[α- * *MeLys(Ac)]-[Lys(Ac)]-NN-NH₂ 611Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]-[α- * **MeLys(Ac)]-ENG-NH₂ 612Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]-[α- * *MeLys(Ac)]-ENA-NH₂ 613Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]-[α- * *MeLeu]-[Lys(Ac)]-NN-NH₂ 614Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]-[α- * *MeLeu]-QNN-NH₂ 615Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]-[Aib]- * *ENN-NH₂ 616Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]-[Aib]- * *[Lys(Ac)]-NN-NH₂ 617Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]-[Aib]- * *[Lys(Ac)]-NQ-NH₂ 522[Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-ENG-NH₂]₂ **** * DIG618 Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Aib]-ENN-NH₂ * *** 619Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[hLeu]-ENA- ********** NH₂ 620Ac-[Pen]-TTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]- * *[Lys(Ac)]-NN-NH₂ 625Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Aib]-[Lys(Ac)]-NN-NH₂ * ** 628Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]- * *[Lys(Ac)]-N-[βAla]-NH₂ 630Ac-[Pen]-NTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Aib]-ENN-NH₂ * *** 631Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[hLeu]-ENA- ********* NH₂ 632Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]- * *[Lys(Ac)]-NN-NH₂ 633Ac-[Pen]-NTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Aib]-[Lys(Ac)]-N-[βAla]- * **NH₂ 634 Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]- * *[Lys(Ac)]-NQ-NH₂ 636Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]- * *[Lys(Ac)]-NA-NH₂ 637Ac-[Pen]-NTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Aib]-[Lys(Ac)]-NN-NH₂ * * 638Ac-[Pen]-NTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Aib]-[Lys(Ac)]-NQ-NH₂ * * 639Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]- * *[Lys(Ac)]-N-[βAla]-NH₂ 640Ac-[Pen]-NTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[hLeu]-[Lys(Ac)]-N- ***** *****[βAla]-NH₂ 641Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[hLeu]- ***** *****[Lys(Ac)]-N-[βAla]-NH₂ 669Ac-[Pen]-QTWQ-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[α-MeVal]-[Lys(Ac)]- ** *NN-NH₂ 534[Ac-[Pen]-QTWQ-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]- ** *NN-NH₂]₂ DIG 1035Ac-[(D)Phe]-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]- * *[Lys(Ac)]-NN-NH₂ 676Ac-[(D)Phe]-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]- ** *[Lys(Ac)]-N-[βAla]-NH₂ 682Ac-[Pen]-NTWQ[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[Aib]-[Lys(Ac)]-NN- ** ****NH₂ 683 Ac-[Pen]-NTWQ[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[4-amino-4-carboxy-** * tetrahydropyran]-Lys(Ac)]-NN-NH₂ 684Ac-[Pen]-NTWQ[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[Achc]-[Lys(Ac)]-NN- * * NH21036 Ac-[Pen]-NTWQ[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[Acvc]-[Lys(Ac)]-NN- * *NH₂ 686Ac-[Pen]-NTWQ[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]- * *NN-NH₂ 688Ac-[Pen]-NTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[4-amino-4-carboxy- * *tetrahydropyran]-[Lys(Ac)]-NN-NH₂ 689Ac-[Pen]-NTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[Achc]-[Lys(Ac)]-NN-NH₂ * **1037 Ac-[Pen]-NTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[Acyc]-[Lys(Ac)]-NN-NH₂** * 731Ac-[Pen]-NTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN- * * NH₂535 [Ac-[Pen]-NTWQ-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[Aib]-KNN-NH₂]₂ DIG **** 536[Ac-[Pen]-NTWQ-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[4-amino-4-carboxy- * *tetrahydropyran]-KNN-NH₂]₂ DIG 537[Ac-[Pen]-NTWQ-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[Achc]-KNN-NH₂]₂ ** *** DIG539 [Ac-[Pen]-NTWQ-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[α-MeLeu]-KNN- ** **NH₂]₂ DIG § the matrix used is 100 fold dilution of standard SIFconcentration * = >360 min; ** = 180-360 minn; *** = 120-180 min; ****= <60-120 min; ***** = <60 min

TABLE 10 Stability of Illustrative Peptides Containing Thioethers Motifand Analogues Within Simulated Intestinal Fluid (SIF) and SimulatedGastric Fluid (SGF) SIF SGF SEQ ID t½ t½ NO: Sequence (min) (min) 692Ac-Cyclo-[[Abu]RTWQC]-YWRKFG-[AEA]-[(D)Lys]-NH₂ ***** 694Ac-Cyclo-[[Abu]-QTWQC]-YWRENG-[AEA]-[(D)Lys]-NH₂ ***** 699Ac-Cyclo-[[Abu]-QTWQC]-YW-[hLeu]-ENG-NH₂ ***** ND 700Ac-Cyclo-[Abu]-QTWQ-(D)Cys]]-YW-[hLeu]-ENG-NH₂ ****§ 701Ac-Cyclo-[[Abu]-QTWQ-[Pen]]-YW-[hLeu]-ENG-NH₂ ***** 703Ac-Cyclo-[[Abu]-QTWQC]-YW-[α-MeLeu]-ENG-NH₂ ***** 704Ac-Cyclo-[[Abu]-QTWQC]-Y-[2-Nal]-[α-MeLys]-ENG-NH₂ ***** 702Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-[2-Nal]-[α- *** ***** MeLys]-ENG-NH₂706 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-[2-Nal]-[α- *** *****MeOrn]-ENG-NH₂ 707 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-W-[α-MeOrn]- ******* ENG-NH₂ 702 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-[2-Nal]-[α- ******* MeLys]-ENG-NH₂ 709Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-W-[α-MeLys]- * *****[Lys(Ac)]-NG-NH₂ 710 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-W-[α-MeLys]- ****** ENG-NH₂ 711 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-[1-Nal]-[α- ****** MeLys]-[Lys(Ac)]-NG-NH₂ 712Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-[2-Nal]-[α- ** *****MeLys]-[Lys(Ac)]-NG-NH₂ 713Ac-Cyclo-[[Abu]-QTWQC]-YW-[α-MeOrn]-[Lys(Ac)]-NG- ** NH₂ 714Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-[2-Nal]-[(D)Asn]- * [Lys(Ac)]-NG-NH₂715 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-Phenoxy)]-[2-Nal]-[α- *MeLys]-[Lys(Ac)]-NG-NH₂ 716Ac-Cyclo-[[Abu]-QTWQC]-[hPhe(3,4-dimethoxy)]-[2-Nal]-[α- **MeLys]-[Lys(Ac)]-NG-NH₂ 717Ac-Cyclo-[[Abu]-QTWQC]-[DMT]-[2-Nal]-[α-MeLys]- * [Lys(Ac)]-NG-NH₂ 718Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-CONH₂)]-[2-Nal]-[α- *** *****MeLys]-[Lys(Ac)]NG-NH₂ 719Ac-Cyclo-[[Abu]-QTWQC]-Phe(3,4-Cl₂)[2-Nal]-[α-MeLys]- ***[Lys(Ac)]NG-NH₂ 720 Ac-Cyclo-[[Abu]-QTWQ-[Pen]]-[Phe(4-OMe)]-[2-Nal]-[α-** *** MeLys]-ENG-NH₂ 721Ac-Cyclo-[[Abu]-QTWQ-[Pen]]-[Phe(4-OMe)]-[2-Nal]-[α- ** ***MeLys]-[Lys(Ac)]NG-NH₂ 782Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-W-[α- * ***MeLys]-ENG-NH₂ 790 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-[2-Nal]-[α- ******** MeOrn]-[Lys(Ac)]-NG-NH₂ 791Ac-Cyclo-[[Abu]-QTWQC]-[2-Nal]-[2-Nal]-[α-MeOrn]- *** ND[Lys(Ac)]-NG-NH₂ 794 Ac-Cyclo-[[Abu]-QTWQC]-[2-Nal]-[2-Nal]-[α-MeLys]-** ND [Lys(Ac)]-NG-NH₂ 797Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-CONH₂)]-[2-Nal]-[α- **** *****MeLys]-[Lys(Ac)]-NG-NH₂ 798Ac-Cyclo-[[Abu]-QTWQC]-[2-Nal]-[2-Nal]-[α-MeLys]-ENG- ** ND NH₂ 810Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-[2-Nal]-[Aib]- * [Lys(Ac)]-NG-NH₂815 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-[2-Nal]-[Orn]- *[Lys(Ac)]-NG-NH₂ 820 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-[2-Nal]-[Chg]-*** [Lys(Ac)]-NG-NH₂ 822Ac-Cyclo-[[Abu]-QTWQC]-[Octgly]-[2-Nal]-[α-MeLys]- *****[Lys(Ac)]-NG-NH₂ 823 Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-[Octgly]-[α-**** MeLys]-[Lys(Ac)]-NG-NH₂ 823Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-[Octgly]-[α- *****MeLys]-[Lys(Ac)]-NG-NH₂ 829Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- * *[α-MeLys]-ENG-NH₂ 857Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- ** *[α-MeLys]-[Lys(Benzoic acid)]-NG-NH₂ 861Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- * *[α-MeLys]-[Lys(isovaleric acid)]-NG-NH₂ 876Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- *** *****[Aib]-[Lys(Ac)]-QG-NH₂ 877Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- *** **[Aib]-QNG-NH₂ 878Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- ***** ***[Aib]-ENG-NH₂ 879 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-1- * *Nal[Aib]-[Lys(Ac)]-NG-NH₂ 880Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- **** *****[Aib]-[Lys(Ac)]-NA-NH₂ 891Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- ** **[α-Me-Orn]-[Lys(Ac)]-NG-NH₂ 892Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- * *[α-MeLys]-[Lys(Ac)]-NG-NH₂ 893Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- *****[Orn]-[Lys(Ac)]-NG-NH₂ 894Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-W- ***** [Orn]-ENG-NH₂895 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-W- *****[Orn]-[Dap]-NG-NH₂ 896Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-W- *****[Orn]-[Dap(Ac)]-NG-NH₂ 897Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- *****[Orn]-[Dap]-NG-NH₂ 898Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- *****[Orn]-[Dap(Ac)]-NG-NH₂ 899Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-W- ***** *****[hLeu]-ENG-NH₂ 900Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-(acetyl-aminoethoxy)]]- ** *****[2-Nal]-[α-MeLys(Ac)]-[Lys(Ac)]-NG-NH₂ 901Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-W-[α- * **Me-Leu]-ENG-NH2 902Succicinyl-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]- * **[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH2 906Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-(acetyl-aminoethoxy)]]- **** *****[2-Nal]-[α-MeLys(Ac)]-ENG-NH₂ 820Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-[2-Nal]-[Chg]- * ** [Lys(Ac)]-NG-NH₂911 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- ** **[α-MeLys]-ENQ-NH₂ 912Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- ** **[α-MeLys]-ENN-NH₂ 913Ac-Cyclo-[[Abu]-TTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- ** **[α-MeLys]-ENG-NH₂ 914Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- **** *****[α-Me-Gly(Ethyl)] Lys(Ac)]-NG-NH₂ 915Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- *** ****[α-MeVal]-[Lys(Ac)]-NG-NH₂ 916Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- ***** ***[α-MeSer]-[Lys(Ac)]-NG-NH₂ 925Ac-(D)Lys-[Cyclo-[[Abu]-QTWQC]]-[Phe(4-OMe)]-[2-Nal]- **** *****[α-MeLeu]-ENG-NH₂ 1039[Ac-[(D)Lys]-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-[2-Nal]- **** *****[α-MeLeu]-ENG-NH₂]₂ DIG: dimerization through (D)Lys 930Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- ***** ND[hLeu]-[Lys(Ac)]-N-[βAla]-NH₂ 933Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- ** **[α-MeLys]-NNG-NH₂ 946Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- **** ****[Aib]-[Lys(Ac)]-NG-NH₂ 955Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- *** *****[α-MeLeu]-[Lys(Ac)]-NN-NH₂ 1040[Ac-Cyclo-[[Abu]-QTWQC]-Y(Bzl)-W-[α-MeLys]-ENG- ** ***** NH₂]₂; PEG25through [α-MeLys] 965Ac-E-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2- * ***Nal]-[α-MeLys]-ENN-NH₂ 966 Ac-(D)Glu-[Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- ***** aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH₂ 967Ac-Arg-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2- ***** ***Nal]-[α-MeLys]-ENN-NH₂ 1041 Ac-[(D)Arg-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- *** aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH₂ 969Ac-F-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2- **** ***Nal]-[α-MeLys]-ENN-NH₂ 970 Ac-[(D)Phe]-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- ***** aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH₂ 972Ac-T-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2- * ***Nal]-[α-MeLys]-ENN-NH₂ 973Ac-Leu-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2- * ***Nal]-[α-MeLys]-ENN-NH₂ 1042 Ac-[(D)Gln]-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2- **** aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH₂ 975Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- ***** *[Acpc]-ENN-NH₂ 976Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- ***** ****[Acbc]-ENN-NH₂ 1043Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- ** *[Acpc]-ENN-NH₂ 978Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- *** *[Acvc]-ENN-NH₂ 979Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- * *[4-amino-4-carboxy-piperidine]-ENN-NH₂ 972Ac-T-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2- * *Nal]-[α-MeLys]-ENN-NH₂ § the matrix used is 100 fold dilution ofstandard SIF concentration * = >360 min; ** = 180-360 minn; ***= 120-180 min; **** = <60-120 min; ***** = <60 min

For each peptide tested, the DTT stability assay was conducted by adding5 μl of a 10 mM peptide stock solution in DMSO to 1 ml of 100 mMTris-C1, pH 7.5 (final peptide concentration is 50 μM). At time 0 min, 5ul of a freshly thawed 100 mM DTT solution was added to the incubationtube containing the peptide, such that the final DTT concentration was0.5 mM. The reactions were incubated at room temperature. At differenttime points up to 120 minutes (20 min, 40 min, 80 min, 120 min), 50 μlaliquots were removed, and the reaction was quenched by adding 10 μl of5M acetic acid. To measure disappearance of the parent peptide, thequenched samples (30p1) were analyzed by reverse phase HPLC and UVabsorbance at 220 nm. The fraction oxidized remaining was graphed versustime, and half-lives were calculated by fitting to a first-orderexponential decay equation using Excel. The results of these studies areshown in Table 11. The peptides having half-life>120 min are allconsidered stable.

TABLE 11 Stability of Illustrative Peptides in DTT Assay DTT SEQ IDStability NO: Sequence (min) 217 Ac-CRTWECYWHEFG-NH₂  <10 1044Ac-CQTWQCYW-[hLeu]-ENG-NH₂ * 1045 Ac-CADWVWCYWHTFGA-[Azt]-[(D)Lys]-NH₂ *1046 Ac-Cyclo-[[Abu]-RTWQC]-YWRKFG-[AEA]-[(D)Lys]-NH₂ >120 549Ac-[[Pen]-QTWQ-[Pen]-YW-[hLeu]-ENG-NH₂ >120 554Ac-[Pen]-QTWQ-[Pen]-YW-[α-MeLeu]-ENG-NH₂ >120 702Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-ENG- >120 NH₂ 557Ac-[Pen]-QTWQ-[Pen]-[Phe(4-Ome)]-[2-Nal]-[α-MeLys]-ENG-NH₂ >120 782Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-W-[α-MeLys]- >120 ENG-NH₂980 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[4- >120amino-4-carboxy-tetrahydropyran]-ENN-NH₂ 534[Ac-[Pen]-QTWQ-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]- >120NN-NH₂]₂ DIG * = 10-120 min

Example 4 Cross-Reactivity of Peptide Inhibitors

The amino acids of the extracellular domain of the human IL-23R are 95%,77% and 70% identical to the cyno IL-23R, rat IL-23R and mouse IL-23R,respectively. Interestingly, the mouse receptor contains an insertion of21 residues that are absent in human, mouse, chimp, dog and cowreceptor. These additional amino acids are located in a region wherehuman IL-23R is thought to bind to IL-23.

To identify peptide inhibitors that cross-reacted with species otherthan human IL-23R, the ability of certain peptide inhibitors to inhibithuman IL-23R, cyno IL-23R, rat IL-23R and mouse IL-23R by ELISA assay.In line with the observation regarding the sequence differences betweenhuman IL-23R and mouse IL-23R, the peptide antagonists tested showed alack of or very weak inhibitory activities in the mouse IL-23R ELISA(see Table 12). In contrast, the antagonists tested to date displayedcomparable potency towards the rat receptor and slightly less activitytowards the cyno receptor.

Various bioassays performed to determine the potency, cross reactivityand the selectivity of IL-23R antagonists are described below.

Assays for Selectivity of Specific IL-23R Antagonists

Human IL-12Rβ1 ELISA

An assay plate was coated with 100 ng/well of human IL-12Rβ1_huFC andincubated overnight at 4° C. The wells were washed, blocked, and washedagain. Serial dilutions of test peptides and IL-23 at a finalconcentration of 2.5 nM were added to each well, and incubated for 2hours at room temperature. After the wells were washed, bound IL-23 wasdetected with goat anti-p40 polyclonal antibodies, followed by an HRPconjugated donkey anti-goat IgG. Signals were visualized with TMB OneComponent HRP Membrane Substrate and quenched with 2 M sulfuric acid.

Mouse IL-23R Competitive Binding ELISA

An assay plate was coated with 50 ng/well of Mouse IL-23R_huFC andincubated overnight at 4° C. The wells were washed, blocked, and washedagain. Serial dilutions of test peptides and IL-23 at a finalconcentration of 4 nM were added to each well, and incubated for 2 hoursat room temperature. After the wells were washed, bound IL-23 wasdetected with goat anti-p40 polyclonal antibodies, followed by an HRPconjugated donkey anti-goat IgG. Signals were visualized with TMB OneComponent HRP Membrane Substrate and quenched with 2 M sulfuric acid.

Rat IL-23R Competitive Binding ELISA

An assay plate was coated with 300 ng/well of Rat IL-23R_huFC andincubated overnight at 4° C. The wells were washed, blocked, and washedagain. Serial dilutions of test peptides and IL-23 at a finalconcentration of 7 nM were added to each well, and incubated for 2 hoursat room temperature. After the wells were washed, bound IL-23 wasdetected with goat anti-p40 polyclonal antibodies, followed by an HRPconjugated donkey anti-goat IgG. Signals were visualized with TMB OneComponent HRP Membrane Substrate and quenched with 2 M sulfuric acid.

Cyno IL-23R Competitive Binding ELISA

An assay plate was coated with 50 ng/well of Cyno IL-23R_huFC andincubated overnight at 4° C. The wells were washed, blocked, and washedagain. Serial dilutions of test peptides and IL-23 at a finalconcentration of 2 nM were added to each well, and incubated for 2 hoursat room temperature. After the wells were washed, bound IL-23 wasdetected with goat anti-p40 polyclonal antibodies, followed by an HRPconjugated donkey anti-goat IgG. Signals were visualized with TMB OneComponent HRP Membrane Substrate and quenched with 2 M sulfuric acid.

TABLE 12 Cross-Reactivity of Illustrative Peptide Inhibitors HumanIL-23R Rodent and Cyno IL-23R Cross Activity (nM) Reactivity (nM) ELISACell Assay ELISA ELISA Cmpd. huIL23R pSTAT3 mouse rat IL23R ELISA cynoNumber IL23 HTRF IL23R IL23 IL23 IL23R IL23 22 + + − + + 197 ++ ND − ++ND 169 ++ ++ − ++ + 198 +++ +++ ND +++ +++ 213 +++ +++ ND +++ ND 219 ++++++ ND +++ ND 230 +++ +++ ND +++ ND +++ indicates 0-250 nM ++ indicates251-1000 nM + indicates 1001-10,000 nM − indicates >25,000 nM

Example 5 NK Cell Assay

Natural killer (NK) cells, purified from human peripheral blood ofhealthy donors by negative selection (Miltenyi Biotech, Cat#130-092-657), were cultured in complete media (RPMI 1640 containing 10%FBS, L-glutamine and penicillin-streptomycin) in the presence of IL-2(RnD, Cat #202-IL-010/CF) at 25 ng/mL. After 7 days, cells werecentrifuged, and resuspended in complete media at 1E6 cells/mL.Recombinant IL-23 at predetermined EC50 to EC75 and IL-18 (RnD, Cat #B003-5) at 10 ng/mL were mixed with varying concentrations of peptides,and added to NK cells seeded at 1E5 cells per well. After 20 to 24hours, IFNγ in the supernatant was quantified using Quantikine ELISA(RnD, Cat # DIF50).

TABLE 13 IC50 of Illustrative Peptide Inhibitors in Primary Cell Line(NK Cell Assay) NK cell SEQ ID assay NO: Sequence (nM) 704Ac-Cyclo-[[Abu]-QTWQC]-Y-[2-Nal]-[α-MeLys]-ENG-NH₂ * 702Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]- * ENG-NH₂ 782Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-W-[α- * MeLys]-ENG-NH₂861 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- *[α-MeLys]-[Lys(isovaleric acid)]-NG-NH₂ 877Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- * [Aib]-QNG-NH₂880 Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- *[Aib]-[Lys(Ac)]-NA-NH₂ 900Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-(acetyl-aminoethoxy)]]-[2- *Nal]-[α-MeLys(Ac)]-[Lys(Ac)]-NG-NH₂ 908Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[Phe(3,4- *OMe₂]-[α-MeLys]-[Lys(Ac)]-NG-NH₂ 911Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- *[α-MeLys]-ENQ-NH₂ 912Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- *[α-MeLys]-ENN-NH₂ 915Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- *[α-MeVal]-[Lys(Ac)]-NG-NH₂ 1038[Ac-Cyclo-[[Abu]-QTWQC]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]- * ENG-NH2]₂; DIGthrough α-MeLys 954Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- *[α-MeLeu)-[Cit]-NN-NH₂ 970Ac-[(D)Phe]-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]- *[2-Nal]-[α-MeLys]-ENN-NH₂ 972Ac-T-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- *[α-MeLys]-ENN-NH₂ 976Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- *[Acbc]-ENN-NH₂ 1043Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- *[Acpc]-ENN-NH₂ 1047Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- *[Achc]-ENN-NH₂ 980Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[4- *amino-4-carboxy-tetrahydropyran]-ENN-NH₂ 984Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]- *[α-MeLeu]-QN-[βAla]-NH₂ 992Ac-(D)Phe-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2- *Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH₂ 993Ac-[(D)Arg]-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]- *[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-ENN-NH₂ * = <25 nM

TABLE 14 IC50 of Illustrative Peptides Containing theAc-[Pen]-XXWX-[Pen]-XXXX Motif and analogues (NK cell assay) SEQ ID NKCell NO: Sequence assay (nM) 602Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]- *[Lys(Ac)]-NN-NH₂ 632Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys(Ac)]- *NN-NH₂ 639Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys(Ac)]- *N-[βAla]-NH₂ 666Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NN- * NH₂668 Ac-[Pen]-QTWQ-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]- *NN-NH₂ 669Ac-[Pen]-QTWQ-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[α-MeVal]-[Lys(Ac)]-NN- **NH₂ 530[Ac-[Pen]-QTWQ[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]-[α-MeVal]- *KNN-NH₂]₂ DIG 531[Ac-[Pen]-QTWQ[Pen]-[Phe[4-(2-acetylaminoethoxy)]-[2-Nal]-K-[Lys(Ac)]- *NN-NH₂]₂ DIG 532[Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NN- *NH₂]₂ DIG 534[Ac-[Pen]-QTWQ-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]- *NN-NH₂]₂ DIG 1048Ac-[(D)Phe]-[Pen]-NTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[4-amino-4-carboxy- *tetrahydropyran]-[Cit]-NN-NH₂ 1049Ac-[(D)Phe]-[Pen]-NTWQ[Pen]-[Phe(4-OMe)]-[2-Nal]-[Achc]-ENN-NH₂ * 1050Ac-[Pen]-NTWQ[Pen]-[Phe(CONH₂)]-[2-Nal]-[Aib]-[Lys(Ac)]-NN-NH₂ * 535[Ac-[Pen]-NTWQ-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[Aib]-KNN-NH₂]₂ DIG * *= <10 nM; ** = 10-25 nM

Example 6 Bioassay Characterization of Peptide Inhibitors

The potency, cross reactivity, and selectivity of certain peptideinhibitors was determined using various bioassays developed for thispurpose and described below.

Rat Splenocyte Assay

A new assay developed was the rat splenocyte assay. This assay examinedthe levels of IL-17A in activated rat splenocytes following stimulationwith IL-23 in the presence of test compound.

Briefly, splenocytes freshly isolated from rat were seeded in 96-welltissue culture plates in complete medium containing concanavalin A.Serial dilutions of test compounds were distributed to each well alongwith rat IL-23 at a final concentration of 4 ng/mL; plates then wereincubated for 3 days at 37° C. in a 5% CO₂ humidified incubator. Changesin IL-17A levels in the supernatants were detected using an ELISA. FIG.1 shows an example of IL-17A levels produced by rat splenocytes inresponse to rat IL-23 stimulation.

Rat Colitis Model: 9 Days of 3% DSS-Containing Drinking Water

There is a body of evidence in the literature supporting the pathogenicrole of IL-23/IL-23R signaling in animal models of colitis. For theIL-23 ligand, this requirement has been shown in multiple models,including an IL-10^(−/−) spontaneous colitis model, a Helicobacterhepaticus-driven colitis model, the anti-CD40 innate colitis model, andthe chronic CD45RB^(high) CD4⁺ T-cell transfer model. For the IL-23receptor, the requirement for colitis development has been shown in theacute models of colitis induced by DSS or by anti-CD40, as well as thechronic CD45RB^(high) CD4⁺ T-cell transfer model. Since certain peptideinhibitors of the present invention do not cross react with the IL-23receptor from mouse but do recognize that from the rat, a rat model ofIBD relevant to the IL-23 pathway was developed.

In this model, colitis was induced in SD rats by 9 days of ad libexposure to drinking water containing 3% DSS. The disease activity index(DAI) score and ratio of colon weight:colon length were compared betweenthree study groups (n=6 rats/group): vehicle, 3% DSS, and 3% DSS withpositive control (sulfasalazine administered at 100 mg/kg PO, QD). TheDAI score consisted of ratings from three parameters, including percentbody weight loss, stool consistency, and a quantitative hemoccult score,and could achieve a maximum value of 3 units. DSS-exposed animalsdisplayed significantly elevated DAI score (compared to vehicle control)from Day 4 onward, with DAI values peaking at approximately 2.5 by theend of the study (Day 9). Treatment of the DSS-exposed rats with thepositive control (sulfasalazine) attenuated the disease score (comparedto DSS alone) from Day 5. The differences observed in the terminal ratioof colon weight:colon length also were significant for DSS-induceddisease animals with and without sulfasalazine treatment.

Ex Vivo Activity and Stability

Two peptides (Compound A and Compound B) were selected for use infurther biological studies (shown below). One contained a thioetherlinkage and the other contained a Pen-Pen disulfide bond. The activity,selectivity and ex vivo stability profiles of the two compounds areprovided herein.

Assays for selectivity of peptide inhibitors included a human IL-12Rb 1ELISA and measurement of the production of IL-12 in PHA activated humanPBMC, which are described briefly below.

Human IL-12Rβ1 ELISA

An assay plate was coated with 100 ng/well of human IL-12Rb 1 huFC andincubated overnight at 4° C. The wells were washed, blocked, and washedagain. Serial dilutions of test peptides and IL-23 at a finalconcentration of 2.5 nM were added to each well, and incubated for 2hours at room temperature. After the wells were washed, bound IL-23 wasdetected with goat anti-p40 polyclonal antibodies, followed by an HRPconjugated donkey anti-goat IgG. Signals were visualized with TMB OneComponent HRP Membrane Substrate and quenched with 2 M sulfuric acid.Data from these assays is provided herein.

Production of IFNγ by IL-12 in PHA Activated Human PBMC

This assay examined the ability of IL-23R antagonists to neutralizeproduction of IFNγ proteins in IL-12-stimulated human PBMCs. IL-23Rpeptide inhibitors specific to the IL-23/IL-23R pathway are not expectedto alter the levels of IFNγ produced. Compound A and Compound B weretested in this assay, and a graph showing that they do not alter thelevels of IFNγ produced at most concentrations tested is provided inFIG. 2.

In Vivo Activity

Acute colitis was induced by feeding female Sprague Dawley rats with 3%(wt/vol) DSS dissolved in drinking water. For nine days starting at thesame day as DSS, Compounds A or B was administered orally three timesper day at 20 mg/kg or 30 mg/kg. Compounds A was also administeredintraperitoneally three times per day at 30 mg/kg. A neutralizinganti-IL-23p19 antibody was used as a comparator, and was administeredintraperitoneally at 4 mg/kg on the same day and fifth day afterstarting DSS. To quantify colitis with clinical activity, diseaseactivity index (DAI) was determined daily for each animal as an averageof three parameters: body weight change (scale 0-3), stool consistency(scale 0-3) and hemoccult blood (scale 0-3), as shown in Table 15. Atnecropsy, the entire colon was removed from the cecum to the rectum. Thecolon was measured for length, flushed with PBS to remove feces,weighed, and opened longitudinally to determine macroscopic score. Thevisible damage of the colon was scored on a scale from 0-3, as shown inTable 16.

Table 17 shows that at Day 7, treatment with Compound A and Bsignificantly improved DAI scores compared to vehicle treated group.FIG. 3 shows results for DAI values from Day 7. In addition, asignificant reduction was also observed in the colon weight to colonlength ratios, and colon macroscopic scores. The reduction ininflammation observed with orally delivered peptides was similar to theeffects observed from neutralizing anti-IL23p19 monoclonal antibody.Statistical analysis for significance was compared to the vehicletreated group and was determined using Student's T-test (GraphPadPrism). Differences were noted as significant *p<0.05, **p<0.01,***p<0.001, ****p<0.0001.

TABLE 15 Scoring of the Disease Activity Index Percent Body StoolHemoccult Score Weight Change Consistency Score 0 None Normal Normal 1 1to 7 Semi solid Guaiac+ 2  8 to 15 Loose Bleeding+ 3 >15 DiarrheaBleeding++

TABLE 16 Scoring of Gross Morphologic Damage of the Colon Score Grossmorphology 0 Normal 1 Erythemia 2 Erythemia, slight edema, smallerosions 3 Two are more bleeding ulcers, inflammation, moderateadhesions 4 Severe ulceration, stenosis with dilations, severe adhesions

TABLE 17 Disease activity index scores and the individual parametersscores at Day 7, colon weight to length ratios and colon macroscopicscores at Day 9. Day 7 Day 9 Necropsy Colon Colon Percent Body WeightStool Hemoccult Weight/Length Macrosopic Change Consistency Score DAI(g/cm) Score Group Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD NoDSS 11.00 2.08**** 0   0**** 0   0**** 0 0****  75.51   7.03*** ND ND 3%DSS, −6.39 1.11   2.00 0.58 1.50 0.50 1.72 0.45  124.36 17.11 1.00 1.00Vehicle Anti- −0.05 1.92**** 1.00  0.58* 0.50 0.5* 0.67 0.43** 99.96 16.19* 0.00 0**  IL23p19 mAb Compound 3.18 2.09**** 1.17 0.90 0.50 0.5*0.56 0.46** 98.38  6.91* 0.00 0**  A, PO Compound 0.13 1.24**** 0.83 0.69* 0.67  0.47* 0.61 0.3*** 97.36  9.32* 0.00 0**  B, PO Compound−0.50 1.88***  1.17 0.69 0.83 0.69 0.83 0.54*  104.32 12.45 0.33 0.47 A,IP

Example 7 In Vitro Assays and Surface Plasmon Resonance (SPR) Analysis

In vitro assays and SPR were performed to further characterize anillustrative compound, Compound C:

Assays described in previous examples were performed to demonstrate thatCompound C is a potent, selective and competitive inhibitor of IL-23R,showing potent inhibition of IL-23-dependent upregulation ofphosphor-STAT3 (pSTAT3) in human DB cells and IFNγ production in humanperipheral blood natural killer (PB NK) cells. In addition, Compound Cwas selective, showing little inhibition in a cell free ELISA for humanIL6R, or in IL-12-dependent production of IFNg in PBMC. Data is shownbelow in Table 18A. Compound C also cross-reacted with cynomolgus IL-23R(IC50 7 nM) and rat IL-23R (IC50 17 nM), and inhibited IL-23-dependentIL-17A production in rat splenocytes (IC50 130 nM) (data not shown).

TABLE 18A In vitro Characterization of Compound C IC50 pSTAT3/DB IFNγ/PBNK IFNγ/IL-12 KD Cell Primary Cell IL-6/IL-6R PBMC Cell IL-23R IL-12Rβ1Assay Assay ELISA Assay Surface Surface Compound 4 nM 27 nM >100 uM >100uM 2.4 nM None C

Compound C exposure was also restricted to the GI following oraladministration to rats does PO at 20 mg/kg, with AUC values of 355ug·h/g for small intestine mucosa; 77 ug·h/g for colon mucosa; and 0.3ug·h/mL for plasma, with a 40% recovery in feces.

Compound C was also stable in a variety of GI fluids and reducingenvironment, having a SIF half-life of >24 h; a SGF half-life of >24 h;a human intestinal fluid half-life of >24 h, and a half-life of >2 h ina DTT assay.

SPR experiments were carried out using a Biacore 2000 instrument andT100 optical biosensors equipped with Biacore CM4 and Xantec HC1500msensor chips. Recombinant human IL-23R_huFC (RnD), or recombinant humanIL-12Rβ1 huFC (RnD) or a mixture of the two receptor subunits werecaptured on an anti-human IgG surface. Recombinant human IL-23(Humanzyme) or Compound C was used as the analyte. SPR sensorgrams werefitted to a one to one interaction model, giving rise to a roughestimate of the association rate constant (k_(on)), dissociation rateconstant (k_(off)) and dissociation constant (K_(D)) of the complexes,as shown in Table 11. The data show that Compound C does not bind toIL-12Rβ1, and binds to IL-23R and the mixed surface of IL-12Rβ1 andIL-23R with similar potency, at 2.42 nM and 2.56 nM, respectively. Thisaffinity for IL-23R is comparable to that from IL-23. In contrast, theaffinity of IL-23 to the mixed surface is approximately 14× faster thanthat from Compound C.

TABLE 18B Binding characteristics of IL-23 and Compound C for IL-12Rβ1,IL-23R or mixed IL-12Rβ1 and IL-23R as determined by SPR. IL-23 CompoundC Surface k_(a)(M−1 sec−1) k_(d) (sec−1) K_(D) (nM) k_(a)(M−1 sec−1)k_(d) (sec−1) K_(D) (nM) IL-12Rb1_huFC 5.01E+05 4.38E−04 0.87 does notbind up to 16.7 uM IL-23R_huFC 7.82E+05 0.00132 1.69 1.37E+07 0.033 2.42IL-12Rb1_huFC/ 6.31E+05 1.15E−04 0.18 1.59E+07 0.041 2.56 IL-23R_huFC

Example 8 Efficacy of Il-23R Antagonists in TNBS Induced Colitis in Rat

To further evaluate the efficacy of IL-23R antagonists in an animalmodel of disease, acute colitis was induced by providing 7-week-oldfemale Sprague-Dawley rats with 60 mg/kg 2,4,6-Trinitrobenzenesulfonicacid (TNBS) in 45%-50% ethanol (TNBS/ethanol) administered intrarectallyat Day 0. Compound C (described in Example 7) was administered orallythree times a day at 20 mg/kg or 6.7 mg/kg and was provided in drinkingwater at 0.6 mg/mL or 0.2 mg/mL, respectively, for 8 days startingapproximately 24 hours (Day −1) prior TNBS inoculation. A neutralizinganti-IL-23p19 antibody was used as a comparator, and was administeredintraperioneally at 4 mg/kg on Day −1 and again on Day 3. All animalsreceived orally PBS (pH 7.4) vehicle which was used to formulateCompound C. The study design in shown in FIG. 5.

To assess the extent of the inflammatory response, animals were observeddaily for clinical signs which included percent body weight loss andsigns of loose stools or diarrhea. Six days after inoculation of TNBS,rats were sacrificed and the entire colon length and colon weight fromcecum to rectum from each animal were recorded. The severity of colitiswas evaluated by a pathologist blinded to the identity of treatments. Inaddition to the colon wall thickness, the gross colon damage was scoredon a 0-4 scale according to Table 19 below, and histopathological scoreswere determined based on below parameters (Tables 20 and 21).

TABLE 19 Definitions for colon macroscopic scores Score Colon GrossMorphology 0 Normal 1 Erythema 2 Erythema, slight edema, small erosions3 Two or more bleeding ulcers, inflammation, moderate adhesions 4 Severeulceration, stenosis with dilations, severe adhesions

TABLE 20 Definitions for histopathology Parameter DefinitionInflammation Extent and severity of inflammatory cells infiltration,localized and/or diffuse involving full thickness of the colon section(transmural). Inflammatory cells include polymorpho-nuclear leukocytes(neutrophils), mononuclear cells (macrophages + lymphopcytes),fibroplasia and neovascularization. Mucosal Necrosis in the mucosa withloss of surface epithelium, Necrosis hemorrhage and cellular debris;measured as the length of the lesion on the total length of the colonsection to determine % area affected Gland Loss % crypt epithelialdegeneration with or without superficial mucosal erosion Colon theaverage thickness of the colon measured transmurally Thickness (fullthickness) from the mucosal surface to the serosa

TABLE 21 Scoring criteria Score Inflammation 0 Normal tissue, noinflammation 0.5 Very minimal localized infiltrates in the superficialmucosa affecting <2% of the colon section 1 Minimal degree of multifocalinfiltrates in the mucosa affecting approximately 2-10% of the colonsection 2 Mild degree of multifocal infiltrates in the mucosa,submucosa, outer muscle band, and serosa affecting approximately 11-25%of the colon section 3 Moderate degree of multifocal infiltrates in themucosa submucosa, outer muscle band and serosa affecting approximately26-50% of the colon section 4 Marked degree of multifocal to diffuseinfiltrates in the mucosa submucosa, outer muscle band and serosaaffecting approximately 51-75% of the colon section 5 Sever degree ofmultifocal to diffuse infiltrates in the mucosa submucosa, outer muscleband and serosa affecting approximately >75% of the colon sectionMucosal Necrosis 0 No Necrosis 0.5 Very minimal and localized regionaffecting <2% of the total colon section 1 Minimal focal to multifocalregions affecting 2-10% of the total colon section 2 Mild focal tomultifocal regions affecting 11-25% of the total colon section 3Moderate focal to multifocal regions affecting 26-50% of the total colonsection 4 Marked focal to multifocal regions affecting 51-75% of thetotal colon section 5 Severe focal to multifocal regions affecting >75%of the total colon section Gland Loss 0 No loss, normal crypt epitheliumand mucosa 0.5 Very minimal loss not exceeding 1-2 regions ofmucosa/gland affected 1 Minimal, 1-10% regions of mucosa/gland affected2 Mild, 11-25% regions of mucosa/gland affected 3 Moderate, 26-50%regions of mucosa/gland affected 4 Marked, 51-75% regions ofmucosa/gland affected 5 Severe, >75% regions of mucosa/gland affectedColon Thickness 0 Normal = <350 microns or less 0.5 Very Minimal =351-400 microns 1 Minimal = 400-500 microns 2 Mild = 501-600 microns 3Moderate = 601-700 microns 4 Marked = 701-800 microns 5 Severe = >801microns

Compared to the sham group, rats challenged with TNBS suffered acuteweight loss, displayed increased incidence of loose stools, andincreased colon weight to length ratio. These data were confirmed by themacroscopic examination of colon which revealed mild colonic injurycharacterized by erythema, edema and small erosions. Treatment withCompound C attenuated these changes as compared to the TNBS colitisgroup. At the high dose, Compound C was significantly effective inreducing the colon weight to length ratio, diminishing the thickness ofthe colon walls, and more importantly, improving the colon grosspathology scores to normal in 70% of the animals. Statisticalsignificances were observed at the low dose in all above indicationsexcept colon wall thickness although a trend was evident. The reductionin inflammation observed with orally delivered Compound C was similar tothe effect observed from the neutralizing anti-IL-23p19 monoclonalantibody (FIG. 6).

Histological examination of H&E stained distal colons show that themajority of the lesions observed from the vehicle group are transmural,characterized by necrosis with inflammatory cells transversing theentire thickness of the colon, presence of necrotic tissue debris on thelumen surface, and mucosa devoid of crypts. The animals treated withCompound C generally showed localized lesions limited in the mucosa andsubmucosa regions, with colon tissues showed potential signs of healingat sites of necrosis (FIG. 7). Specifically, the animals treated with160 mg/kg/d Compound C showed a significant reduction in inflammation,mucosal necrosis and colon wall thickness leading to a significantreduction in the overall histological score, comparable to that from theanti-IL-23p19 antibody control (FIG. 8).

Concentration analysis of samples collected 1 hour post the last PO doseshow that the plasma concentrations of Compound C detected from allanimals are <=2X below the IC75 of the compounds as determined in therat splenocyte/IL-17A cell based assay or the rat IL-23R ELISA,suggesting that the efficacies observed from oral treatment are mostlikely due to its local activity at the colon (FIG. 9). Collectively,these data highlights the protective effect of an IL-23R antagonist inthe development of TNBS colitis.

These studies demonstrate that peptides of the present invention arepotent, selective and orally efficacious ILweR peptide antagonists thatare promising therapeutics for the treatment of IBD and other disorders.As shown herein, the present invention provides peptides that are:potent blockers of IL-23/IL-23R signaling in a human cell line and inhuman primary cells; selective for IL-23R, and do not inhibit binding toIL-6R or signaling through IL-12R; cross-reactive towards rat andcynomolgus but not mouse homologs, enabling in vivo studies in thesespecies; resistant to proteolytic and reducing environments of the GI,resulting in high drug levels in the intestinal tissues and limited drugconcentrations in the circulation, offering potential safety advantagesover systemically delivered therapeutics; and effective and comparableto an anti-IL23p19 monoclonal antibody in attenuating colitis in aTNBS-induced rat colitis model, most like through GI-restrictedactivities.

All of the above U.S. patents, U.S. patent application publications,U.S. patent applications, foreign patents, foreign patent applicationsand non-patent publications referred to in this specification and/orlisted in the Application Data Sheet, are incorporated herein byreference, in their entirety.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

1.-46. (canceled)
 47. A method for treating an Inflammatory Bowel Disease (IBD) in a subject, comprising providing to the subject an effective amount of a pharmaceutical composition comprising a peptide inhibitor of an interleukin-23 receptor, or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor comprises an amino acid sequence of Formula (Ir): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (Ir) wherein X1 is any amino acid or absent; X2 is any amino acid or absent; X3 is any amino acid or absent; X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, Asp, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Sec, 2-chloromethylbenzoic acid, mercapto-propanoic acid, mercapto-butyric acid, 2-chloro-acetic acid, 3-choro-propanoic acid, 4-chloro-butyric acid, 3-chloro-isobutyric acid, Abu, β-azido-Ala-OH, propargylglycine, 2-(3′-butenyl)glycine, 2-allylglycine, 2-(3′-butenyl)glycine, 2-(4′-pentenyl)glycine, or 2-(5′-hexenyl)glycine; X5 is any amino acid; X6 is any amino acid; X7 is Trp, Glu, Gly, Ile, Asn, Pro, Arg, Thr or OctGly, or a corresponding α-methyl amino acid form of any of the foregoing; X8 is any amino acid; X9 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Asp, Leu, Val, Phe, Ser, Sec, Abu, β-azido-Ala-OH, propargylglycine, 2-2-allylglycine, 2-(3′-butenyl)glycine, 2-(4′-pentenyl)glycine, Ala, hCys, Met, MeCys, (D)Tyr or 2-(5′-hexenyl)glycine; X10 is Tyr, Phe(4-OMe), 1-Nal, 2-Nal, Aic, α-MePhe, Bip, (D)Cys, Cha, DMT, (D)Tyr, Glu, His, hPhe(3,4-dimethoxy), hTyr, N-Me-Tyr, Trp, Phe(4-CONH₂), Phe(4-phenoxy), Thr, Tic, Tyr(3-tBu), Phe(4-tBu), Phe(4-CN), Phe(4-Br), Phe(4-NH₂), Phe(4-F), Phe(3,5-F₂), Phe(4-CH₂CO₂H), Phe(penta-F), Phe(3,4-Cl), Phe(4-CF₃), Bip, Cha, 4-PyridylAlanine, βhTyr, OctGly, Phe(4-N₃), Phe(4-Br), Phe[4-(2-aminoethoxy)], Phe, a Phe analog, a Tyr analog, or a corresponding α-methyl amino acid form of any of the foregoing; X11 is 2-Nal, 1-Nal, 2,4-dimethylPhe, Bip, Phe(3,4-Cl₂), Phe (3,4-F₂), Phe(4-CO₂H), βhPhe(4-F), α-Me-Trp, 4-phenylcyclohexyl, Phe(4-CF₃), Phe(3,4-OMe₂), α-MePhe, βhPhe, βhTyr, βhTrp, Nva(5-phenyl), Phe, His, hPhe, Tqa, Trp, Tyr, Phe(4-OMe), Phe(4-Me), Trp(2,5,7-tri-tert-Butyl), Phe(4-Oallyl), Tyr(3-tBu), Phe(4-tBu), Phe(4-guanidino), Phe(4-OBzl), Glu(Bzl), 4-Phenylbenzylalanine, Phe[4-(2-aminoethoxy)], 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, 1,2,3,4-tetrahydro-norharman, Phe(4-CONH₂), Phe(3,4-Dimethoxy), Phe(2,3-Cl₂), Phe(2,3-F₂), Phe(4-F), 4-phenylcyclohexylalanine or Bip; X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, α-MeLys, D-Ala, (D)Asn, (D)Asp, (D)Leu, (D)Phe, (D)Tyr, Aib, α-MeLeu, α-MeOrn, β-Aib, βhAla, βhArg, βhLeu, βhVal, β-spiro-pip, Glu, hArg, Ile, Lys, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Ser, Thr, Tle, t-butyl-Gly, 4-amino-4-carboxy-tetrahydropyran (THP), Achc Acpc, Acbc, Acvc, Agp, Aib, α-DiethylGly, α-MeLys(Ac), α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D)Asn, Glu, hArg, or Lys, or a corresponding α-methyl amino acid form of any of the foregoing; X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Asn, Cit, Lys, Arg, Orn, Val, βhAla, Lys(Ac), (D)Asn, (D)Leu, (D)Phe, (D)Thr, Ala, α-MeLeu, Aib, β-Glu, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Dab, Dap, α-DiethylGly, hLeu, Asn, Ogl, Pro, Gln, Ser, β-spiro-pip, Thr, Tba, Tle or Aib, or a corresponding α-methyl amino acid form of any of the foregoing; X14 is Phe, Tyr, Glu, Gly, His, Lys, Leu, Met, Asn, Lys(Ac), Dap(Ac), Asp, Pro, Gln, Arg, Ser, Thr, Tic or βhPhe, or a corresponding α-methyl amino acid form of any of the foregoing; X15 is Gly, Ser, Thr, Gln, Ala, (D)Ala, (D)Asn, (D)Asp, (D)Leu, (D)Phe, (D)Thr, Aea, Asp, Asn, Glu, Phe, Gly, Lys, Leu, Pro, Arg, β-Ala, or Sarc, or a corresponding α-methyl amino acid form of any of the foregoing; X16 is any amino acid or absent; X17 is any amino acid or absent; X18 is any amino acid or absent; X19 is any amino acid or absent; and X20 is any amino acid or absent, wherein the peptide inhibitor is cyclized via a bond between X4 and X9, and wherein the peptide inhibitor inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor.
 48. The method of claim 47, wherein the pharmaceutical composition is provided to the subject by an oral route of administration. 49.-55. (canceled)
 56. The method of claim 47, wherein the IBD is ulcerative colitis.
 57. The method of claim 47, wherein the IBD is Crohn's disease.
 58. The method of claim 47, wherein the IBD is pouchitis after an ileoanal anastomosis.
 59. The method of claim 47, wherein the bond between X4 and X9 is a disulfide bond, a thioether bond, a lactam bond, a triazole ring, a selenoether bond, a diselenide bond, or an olefin bond.
 60. The method of claim 47, wherein X4 is Pen and X9 is Pen, and the bond is a disulfide bond.
 61. The method of claim 59, wherein X7 is Trp; X10 is Phe, Tyr, a Phe analog, or a Tyr analog; X11 is Trp, 1-Nal, 2-Nal, Phe(3,4-Cl₂), Phe(3,4-F₂), Phe(4-CONH₂), or Phe(3,4-Dimethoxy); and X12 is Aib, α-Me-Lys, α-Me-Val, α-Me-Leu; Achc, Acvc, Acpc, or 4-amino-4-carboxy-tetrahydropyran (THP).
 62. The method of claim 59, wherein the Phe analog is Phe(4-OBzl), Phe(4-OMe), Phe(4-CONH₂), Phe(3,4-Cl₂), Phe(4-tBu), Phe(4-NH₂), Phe(4-Br), Phe(4-CN), Phe(4-CO₂H), Phe(4-(2-aminoethoxy)) or Phe(4-guanidino).
 63. The method of claim 59, wherein the peptide inhibitor comprises any of the following amino acid sequences: (SEQ ID NO: 282) Ac-[Pen]-Q-T-W-Q-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-Me-Lys]-ENG-NH₂; (SEQ ID NO: 283) Ac-[Pen]-N-T-W-Q-[Pen]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Aib]-[Lys(Ac)]-NN-NH₂; (SEQ ID NO: 285) Ac-[Pen]-Q-T-W-Q-[Pen]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH₂; (SEQ ID NO: 668) Ac-[Pen]-QTWQ-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NN-NH₂; (SEQ ID NO: 603) Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLeu]-QNN-NH₂; (SEQ ID NO: 286) Ac-[Pen]-Q-T-W-Q-[Pen]-[Phe(4-CONH₂)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NN-NH₂; (SEQ ID NO: 598) Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂; (SEQ ID NO: 1034) Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NN-NH₂; (SEQ ID NO: 601) Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENA-NH₂; (SEQ ID NO: 602) Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH₂; (SEQ ID NO: 603) Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLeu]-QNN-NH₂; (SEQ ID NO: 604) Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Aib]-ENN-NH₂; (SEQ ID NO: 605) Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-Aib-[Lys(Ac)]-NN-NH₂; (SEQ ID NO: 606) Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Aib]-[Lys(Ac)]-NQ-NH₂; (SEQ ID NO: 613) Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH₂; (SEQ ID NO: 614) Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]]-[2-Nal]-[α-MeLeu]-QNN-NH₂; (SEQ ID NO: 639) Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Aib]-[Lys(Ac)]-N-[βAla]-NH₂; (SEQ ID NO: 641) Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[hLeu]-[Lys(Ac)]-N-[βAla]-NH₂; (SEQ ID NO: 616) Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]]-[2-Nal]-[Aib]-[Lys(Ac)]-NN-NH₂; (SEQ ID NO: 632) Ac-[Pen]-NTWQ-[Pen]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Aib]-[Lys(Ac)]-NN-NH₂; (SEQ ID NO: 617) Ac-[Pen]-QTWQ-[Pen]-[Phe[4-(2-acetylaminoethoxy)]]-[2-Nal]-[Aib]-[Lys(Ac)]-NQ-NH₂; or (SEQ ID NO: 623) Ac-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[Aib]-[Lys(Ac)]-NQ-NH₂,

wherein the peptide inhibitor comprises a disulfide bond between the two Pen amino acids.
 64. The method of claim 47, wherein X4 is Abu, 2-chloromethylbenzoic acid, mercapto-propanoic acid, mercapto-butyric acid, 2-chloro-acetic acid, 3-chloro-propanoic acid, 4-chloro-butyric acid, 3-chloro-isobutyric acid; X9 is Abu, Cys, Pen, hCys, D-Pen, D-Cys, or D-hCys, and and the bond between X4 and X9 is a thioether bond.
 65. The method of claim 64, wherein (a) X4 is Abu and X9 is Cys; or (b) X4 is Cys and X9 is Abu, wherein the peptide inhibitor is cyclized via a thioether bond between X4 and X9.
 66. The method of claim 64, wherein X7 is Trp; X10 is Phe, Tyr, a Phe analog, or a Tyr analog; X11 is Trp, 1-Nal, 2-Nal, Phe(3,4-Cl₂), Phe(3,4-F₂), Phe(4-CONH₂), or Phe(3,4-Dimethoxy); and X12 is α-Me-Lys, α-Me-Leu, α-Me-Ser, α-Me-Val, Achc, Acvc, Acpc, Acbc or 4-amino-4-carboxy-tetrahydropyran.
 67. The method of claim 66, wherein the Phe analog is Phe(4-OBzl), Phe(4-OMe), Phe(4-CONH₂), Phe(3,4-Cl₂), Phe(4-tBu), Phe(4-NH₂), Phe(4-Br), Phe(4-CN), Phe(4-CO₂H), Phe(4-(2aminoethoxy)) or Phe(4-guanidino)
 68. The peptide inhibitor of claim 64, wherein the peptide inhibitor comprises any of the following amino acid sequences: (SEQ ID NO: 430) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-E-N-G; (SEQ ID NO: 431) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe(4-OMe)]-[2-Nal]-[α-MeOrn]-ENG-NH₂; (SEQ ID NO: 432) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe(4-CO₂H)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂; (SEQ ID NO: 433) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂; (SEQ ID NO: 434) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe(4-CONH₂)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]NG-NH₂; (SEQ ID NO: 435) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NA-NH₂; (SEQ ID NO: 436) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NAE-NH₂; (SEQ ID NO: 437) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENG-NH₂; (SEQ ID NO: 439) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-DNG-NH₂; (SEQ ID NO: 440) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Lys(succinic acid)]- NG-NH₂; (SEQ ID NO: 441) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Lys(glutaric acid)]- NG-NH₂; (SEQ ID NO: 442) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Lys(pyroglutamic acid)]-NG-NH₂; (SEQ ID NO: 443) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Lys(isovaleric acid)]- NG-NH₂; (SEQ ID NO: 444) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG- [(D)Lys]-NH₂; (SEQ ID NO: 445) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-[AEA]- NH₂; (SEQ ID NO: 446) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Aib]-QNG-NH₂; (SEQ ID NO: 447) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Aib]-[Lys(Ac)]-NA-NH₂; (SEQ ID NO: 448) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Aib]-KNG-NH₂; (SEQ ID NO: 449) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂; (SEQ ID NO: 656) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-(acetyl-aminoethoxy)]]-[2-Nal]-[α-MeLys(Ac)]-[Lys(Ac)]- NG-NH₂; (SEQ ID NO: 657) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-(acetyl-aminoethoxy)]]-[2-Nal]-[α-MeLys(Ac)]-ENG-NH₂; (SEQ ID NO: 658) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[4-amino-4-carboxy- tetrahydropyran]-ENN-NH₂; (SEQ ID NO: 659) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENQ-NH₂; (SEQ ID NO: 912) Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH₂; (SEQ ID NO: 660) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeVal]-[Lys(Ac)]-NG-NH₂; (SEQ ID NO: 661) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[hLeu]-[Lys(Ac)]-N-[βAla]-NH₂; (SEQ ID NO: 662) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-(acetyl-aminoethoxy)]]-[2-Nal]-[α-MeLys(Ac)]-ENQ-NH₂; (SEQ ID NO: 663) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-(acetyl-aminoethoxy)]]-[2-Nal]-[α-MeLys(Ac)]-ENN-NH₂; (SEQ ID NO: 664) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLeu]-ENN-NH₂; (SEQ ID NO: 665) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLeu)-[Cit]-NN-NH₂; (SEQ ID NO: 766) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]-NN-NH₂; (SEQ ID NO: 767) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Aib]-[Lys(Ac)]-NG-NH₂; (SEQ ID NO: 965) Ac-E-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH₂; (SEQ ID NO: 966) Ac-(D)Glu-[Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH₂; (SEQ ID NO: 967) Ac-Arg-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH₂; (SEQ ID NO: 1041) Ac-[(D)Arg-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH₂; (SEQ ID NO: 969) Ac-F-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH₂; (SEQ ID NO: 970) Ac-[(D)Phe]-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH₂; (SEQ ID NO: 971) Ac-[2-Nal]-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH₂; (SEQ ID NO: 973) Ac-Leu-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH₂; (SEQ ID NO: 1042) Ac-[(D)Gln]-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH₂; (SEQ ID NO: 842) Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLeu]-ENG-NH₂; (SEQ ID NO: 972) Ac-T-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLys]-ENN-NH₂; (SEQ ID NO: 752) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[α-MeLeu]-QN-[βAla]-NH₂; (SEQ ID NO: 753) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Acbc]-ENN-NH₂; (SEQ ID NO: 754) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Achc]-ENN-NH₂; (SEQ ID NO: 755) Ac-Cyclo-[[Abu]-QTWQC]]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[Acvc]-ENN-NH₂; (SEQ ID NO: 979) Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[4-amino-4-carboxy-piperidine]- ENN-NH₂; (SEQ ID NO: 993) Ac-[(D)Arg]-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[4-amino-4-carboxy- tetrahydropyran]-ENN-NH₂; or (SEQ ID NO: 980) Ac-Cyclo-[[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]]-[2-Nal]-[4-amino-4-carboxy- tetrahydropyran]-ENN-NH₂,

wherein the peptide inhibitor comprises a thioether bond between the Abu and the C.
 69. A method for treating an Inflammatory Bowel Disease (IBD) in a subject, comprising providing to the subject an effective amount of a pharmaceutical composition comprising a peptide inhibitor of an interleukin-23 receptor, or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor comprises the amino acid sequence of Formula IIIa: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20  (IIIa) wherein X1 is any amino acid or absent; X2 is any amino acid or absent; X3 is any amino acid or absent; X4 is Abu, Pen, or Cys; X5 is any amino acid or absent; X6 is any amino acid or absent; X7 is Trp, Bip, Gln, His, Glu(Bzl), 4-Phenylbenzylalanine, Tic, Phe[4-(2-aminoethoxy)], Phe(3,4-Cl₂), Phe(4-OMe), 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, α-MeTrp, 1,2,3,4-tetrahydro-norharman, Phe(4-CO₂H), Phe(4-CONH₂), Phe(3,4-Dimethoxy), Phe(4-CF₃), ββ-diPheAla, Phe(4-tBu), Glu, Gly, Ile, Asn, Pro, Arg, Thr or Octgly, or a corresponding α-methyl amino acid form of any of the foregoing; X8 is any amino acid or absent; X9 is Abu, Pen, or Cys; X10 is 1-Nal, 2-Nal, Aic, Bip, (D)Cys, Cha, DMT, (D)Tyr, Glu, Phe, His, Trp, Thr, Tic, Tyr, 4-pyridylAla, Octgly a Phe analog or a Tyr analog, or a corresponding α-methyl amino acid form of any of the foregoing; X11 is 2-Nal, 1-Nal, 2,4-dimethylPhe, Bip, 4-phenylcyclohexyl, Glu(Bzl), 4-Phenylbenzylalanine, Phe[4-(2-aminoethoxy)], Phe(3,4-Cl₂), Phe(3,4-F₂), βhPhe(4-F), Phe(4-OMe), 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, α-MeTrp, 1,2,3,4-tetrahydro-norharman, Phe(4-CO₂H), Phe(4-CONH₂), Phe(3,4-Dimethoxy), Phe(4-CF₃), Phe(2,3-Cl₂), Phe(2,3-F₂), Phe(4-F), 4-phenylcyclohexylalanine, α-MePhe, βhNal, βhPhe, βhTyr, βhTrp, Bip, Nva(5-phenyl), Phe, His, hPhe, Tqa, Trp, Tyr, Phe(4-Me), Trp(2,5,7-tri-tertButyl), Phe(4-OAllyl), Tyr(3-tBu), Phe(4-tBu), Phe(4-guanidino), or Phe(4-OBzl); X12 is α-MeLys, α-MeOrn, α-MeLeu, MeLeu, Aib, Achc, Acvc, Acpc, 4-amino-4-carboxy-tetrahydropyran (THP), (D)Ala, (D)Asn, (D)Leu, (D)Asp, (D)Phe, (D)Thr, 3-Pal, Aib, β-Ala, βhGlu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Dab, Dap, α-DiethylGly, Glu, Phe, hLeu, hArg, hLeu, Ile, Lys, Leu, Asn, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Arg, Ser, Thr or Tle, or a corresponding α-methyl amino acid form of any of the foregoing; X13 is Lys(Ac), (D)Asn, (D)Leu, (D)Thr, (D)Phe, Ala, Aib, α-MeLeu, βAla, βhGlu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Arg, Orn, Dab, Dap, α-DiethylGly, Glu, Phe, hLeu, Lys, Leu, Asn, Ogl, Pro, Gln, Asp, Arg, Ser, spiro-pip, Thr, Tba, Tlc, Val or Tyr, or a corresponding α-methyl amino acid form of any of the foregoing; X14 is Asn, Glu, Phe, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic or Tyr, or a corresponding α-methyl amino acid form of any of the foregoing; X15 is Gly, (D)Ala, (D)Asn, (D)Asp, Asn, (D)Leu, (D)Phe, (D)Thr, Ala, (2-aminoethoxy)acetic acid (AEA), Asp, Glu, Phe, Gly, Lys, Leu, Pro, Gln, Arg or Ser, or a corresponding α-methyl amino acid form of any of the foregoing; X16 is absent, Gly, Ala, Asp, Ser, Pro, Asn or Thr, or a corresponding α-methyl amino acid form of any of the foregoing; X17 is absent, Glu, Ser, Gly or Gln, or a corresponding α-methyl amino acid form of any of the foregoing; X18 is absent or any amino acid; X19 is absent or any amino acid; and X20 is absent or any amino acid, wherein the peptide inhibitor is cyclized via an intramolecular bond between X4 and X9.
 70. The method of claim 69, wherein X4 or X9 is Abu.
 71. The method of claim 68, wherein the amino acid sequence of the peptide inhibitor comprises one or more, two or more, or three of the following: X5 is Arg, Gln, Dap or Orn; X6 is Thr or Ser; and X8 is Gln, Val, Phe, Glu or Lys.
 72. The method of claim 69, wherein the amino acid sequence of the peptide inhibitor comprises one or more, two or more, three or more, four or more, five or more, six or more, or seven of the following: X10 is Tyr or a Phe analog; X11 is Trp, 2-Nal, 1-Nal, Phe(4-OAllyl), Tyr(3-tBu), Phe(4-tBu), Phe(4-guanidino), Phe(4-OMe), 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, α-MeTrp or 1,2,3,4-tetrahydro-norharman; X12 is Arg, hLeu, (D)Asn, Aib, α-MeLys, α-MeLeu, α-MeOrn, Achc, Acvc, Acpc, Acpc, or THP; X13 is Lys, Glu or Lys(Ac); X14 is Phe or Asn; X15 is Gly, Ser, Asn, or Ala; and X16 is absent.
 73. The method of claim 69, wherein the Phe analog is Phe(4-OBzl), Phe(4-OMe), Phe(4-CONH₂), Phe(3,4-Cl₂), Phe(4-tBu), Phe(4-NH₂), Phe(4-Br), Phe(4-CN), Phe(4-CO₂H), Phe(4-(2aminoethoxy)) or Phe(4-guanidino).
 74. The method of claim 69, wherein the IBD is Crohn's disease.
 75. The method of claim 69, wherein the IBD is ulcerative colitis.
 76. The method of claim 69, wherein the IBD is pouchitis after an ileoanal anastomosis.
 77. The method of claim 69, wherein the peptide inhibitor of the interleukin-23 receptor, or the pharmaceutically acceptable salt or solvate thereof, is provided to the subject orally. 